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Yin H, Dong X, Liu T. Identification of novel AURKA inhibitors against neuroblastoma using a virtual screening approach. Bioorg Chem 2025; 160:108480. [PMID: 40253760 DOI: 10.1016/j.bioorg.2025.108480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/04/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025]
Abstract
This study aims to screen and validate AURKA inhibitors to provide lead compounds and theoretical foundations for targeted therapy of neuroblastoma (NB). Through computer-aided drug screening, 11 compounds effectively binding to AURKA were selected from the YaTCM database, and their toxicity was predicted using admetSAR. Subsequently, molecular dynamics (MD) simulations were employed to evaluate the binding affinity and complex stability of the compounds with AURKA, leading to the identification of four preferred compounds (Erylatissin B, (+)-khellactone, Brazilin, and hematoxylin). Further steered molecular dynamics (SMD) and umbrella sampling (US) simulations were conducted to calculate the dissociation energy, confirming their binding strength with AURKA. In vitro experiments demonstrated that Brazilin significantly inhibited proliferation, migration, and induced apoptosis in SK-N-BE (2) cells, while also suppressing AURKA protein expression and its interaction with N-Myc. In vivo experiments showed that Brazilin markedly inhibited tumor growth in a mouse NB model. The findings indicate that Brazilin, by targeting AURKA, exhibits potential anti-NB activity, offering a new candidate compound and theoretical support for NB treatment.
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Affiliation(s)
- Hongli Yin
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215003, China.
| | - Xue Dong
- Department of Pharmaceutics, Dalian Women and Children's Medical Group, Dalian, Liaoning 116012, China
| | - Tianyi Liu
- Department of Pharmaceutics, Dalian Women and Children's Medical Group, Dalian, Liaoning 116012, China.
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Verma A, Bharatiya P, Jaitak A, Nigam V, Monga V. Advances in the design, discovery, and optimization of aurora kinase inhibitors as anticancer agents. Expert Opin Drug Discov 2025; 20:475-497. [PMID: 40094219 DOI: 10.1080/17460441.2025.2481272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
INTRODUCTION Aurora kinases (AKs) play key roles during carcinogenesis and show a close relationship with many cellular effects including mitotic entry, spindle assembly and chromosomal alignment biorientation. Indeed, elevated levels of AKs have been reported in several different tumor types, leading research scientists to investigate ways that we can target AKs for the purpose of developing new anticancer therapeutics. AREA COVERED This review examines the design, discovery, and development of Aurora kinase inhibitors (AKIs) as anticancer agents and delineates their roles in cancer progression or development. Various databases like PubMed, Scopus, Google scholar, SciFinder were used to search the relevant information. This article provides a comprehensive overview of recent advances in the medicinal chemistry of AKIs including the candidates under clinical development and list of patents filed. In addition, their mechanistic findings, SARs, and in silico studies have also been discussed to offer prospects in this field. EXPERT OPINION The integration of artificial intelligence and computational approaches is poised to accelerate the development of AKIs as anticancer agents. However, the associated challenges currently hindering its impact in drug development must be overcome before drugs can successfully translate from early drug development into clinical practice.
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Affiliation(s)
- Anubhav Verma
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
| | - Pradhuman Bharatiya
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
| | - Aashish Jaitak
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
| | - Vaibhav Nigam
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
| | - Vikramdeep Monga
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
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Chen H, Li M, Zhang Y, Song M, Que Y, Wang J, Sun F, Zhu J, Huang J, Liu J, Xu J, Lu S, Zhang Y. AURKB inhibition induces rhabdomyosarcoma apoptosis and ferroptosis through NPM1/SP1/ACSL5 axis. JCI Insight 2025; 10:e182429. [PMID: 39927464 PMCID: PMC11948576 DOI: 10.1172/jci.insight.182429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 12/19/2024] [Indexed: 02/11/2025] Open
Abstract
Rhabdomyosarcoma (RMS) is one of the most common solid tumors in children and adolescents. Patients with relapsed/refractory RMS have limited treatment options, highlighting the urgency for the identification of novel therapeutic targets for RMS. In the present study, aurora kinase B (AURKB) was found to be highly expressed in RMS and associated with unfavorable prognosis of patients. Functional experiments indicated that inhibition of AURKB significantly reduced RMS cell proliferation, induced apoptosis and ferroptosis, and suppressed RMS growth in vivo. The highly expressed AURKB in RMS contributes to the apoptosis and ferroptosis resistance of tumor cells through the nucleophosmin 1 (NPM1)/Sp1 transcription factor (SP1)/acyl-CoA synthetase long-chain family member 5 (ACSL5) axis. Furthermore, inhibition of AURKB exerted an anti-RMS effect together with vincristine both in vitro and in vivo, with tolerable toxicity. The above findings provide insights we believe are new into the tumorigenesis of RMS, especially with regard to apoptosis or ferroptosis resistance, indicating that AURKB may be a potential target for clinical intervention in patients with RMS.
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Affiliation(s)
- Huimou Chen
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Oncology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mengzhen Li
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu Zhang
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mengjia Song
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yi Que
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Juan Wang
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Feifei Sun
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jia Zhu
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Junting Huang
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Juan Liu
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiaqian Xu
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Suying Lu
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yizhuo Zhang
- Department of Pediatric Oncology and
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Kalitin N, Koroleva N, Lushnikova A, Babaeva M, Samoylenkova N, Savchenko E, Smirnova G, Borisova Y, Kostarev A, Karamysheva A, Pavlova G. N-Glycoside of Indolo[2,3- a]pyrrolo[3,4- c]carbazole LCS1269 Exerts Anti-Glioblastoma Effects by G2 Cell Cycle Arrest and CDK1 Activity Modulation: Molecular Docking Studies, Biological Investigations, and ADMET Prediction. Pharmaceuticals (Basel) 2024; 17:1642. [PMID: 39770484 PMCID: PMC11676706 DOI: 10.3390/ph17121642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/28/2024] [Accepted: 11/29/2024] [Indexed: 01/04/2025] Open
Abstract
Background/Objectives: Indolo[2,3-a]pyrrolo[3,4-c]carbazole scaffold is successfully used as an efficient structural motif for the design and development of different antitumor agents. In this study, we investigated the anti-glioblastoma therapeutic potential of glycosylated indolocarbazole analog LCS1269 utilizing in vitro, in vivo, and in silico approaches. Methods: Cell viability was estimated by an MTT assay. The distribution of cell cycle phases was monitored using flow cytometry. Mitotic figures were visualized by fluorescence microscopy. Quantitative RT-PCR was used to evaluate the gene expression. The protein expression was assessed by Western blotting. Molecular docking and computational ADMET were approved for the probable protein target simulations and predicted pharmacological assessments, respectively. Results: Our findings clearly suggest that LCS1269 displayed a significant cytotoxic effect against diverse glioblastoma cell lines and patient-derived glioblastoma cultures as well as strongly suppressed xenograft growth in nude mice. LCS1269 exhibited more potent anti-proliferative activity toward glioblastoma cell lines and patient-derived glioblastoma cultures compared to conventional drug temozolomide. We further demonstrated that LCS1269 treatment caused the severe G2 phase arrest of cell cycle in a dose-dependent manner. Mechanistically, we proposed that LCS1269 could affect the CDK1 activity both by targeting active site of this enzyme and indirectly, in particular through the modulation of the Wee1/Myt1 and FOXM1/Plk1 signaling pathways, and via p21 up-regulation. LCS1269 also showed favorable pharmacological characteristics in in silico ADME prediction in comparison with staurosporine, rebeccamycin, and becatecarin as reference drugs. Conclusions: Further investigations of LCS1269 as an anti-glioblastoma medicinal agent could be very promising.
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Affiliation(s)
- Nikolay Kalitin
- Laboratory of Tumor Cell Genetics, N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia;
| | - Natalia Koroleva
- Laboratory of Oncogenomics, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (N.K.); (A.L.)
| | - Anna Lushnikova
- Laboratory of Oncogenomics, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (N.K.); (A.L.)
| | - Maria Babaeva
- Molecular Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Nadezhda Samoylenkova
- Laboratory of Molecular and Cellular Neurogenetics, N.N. Burdenko National Medical Research Center of Neurosurgery, 125047 Moscow, Russia; (N.S.); (E.S.); (G.P.)
| | - Ekaterina Savchenko
- Laboratory of Molecular and Cellular Neurogenetics, N.N. Burdenko National Medical Research Center of Neurosurgery, 125047 Moscow, Russia; (N.S.); (E.S.); (G.P.)
| | - Galina Smirnova
- Laboratory of Biochemical Pharmacology and Tumor Models, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (G.S.); (Y.B.)
| | - Yulia Borisova
- Laboratory of Biochemical Pharmacology and Tumor Models, N.N. Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia; (G.S.); (Y.B.)
| | - Alexander Kostarev
- Max Planck Institute for Biology, University of Tübingen, 72074 Tübingen, Germany;
| | - Aida Karamysheva
- Laboratory of Tumor Cell Genetics, N.N. Blokhin National Medical Research Center of Oncology, Kashirskoe Shosse 24, 115478 Moscow, Russia;
| | - Galina Pavlova
- Laboratory of Molecular and Cellular Neurogenetics, N.N. Burdenko National Medical Research Center of Neurosurgery, 125047 Moscow, Russia; (N.S.); (E.S.); (G.P.)
- Laboratory of Neurogenetics and Developmental Genetics, Institute of Higher Nervous Activity and Neurophysiology of RAS, 117485 Moscow, Russia
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Zhang K, Wei J, Zhang S, Fei L, Guo L, Liu X, Ji Y, Chen W, Ciamponi FE, Chen W, Li M, Zhai J, Fu T, Massirer KB, Yu Y, Lupien M, Wei Y, Arrowsmith CH, Wu Q, Tan W. A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer. Cell Chem Biol 2024; 31:1942-1957.e6. [PMID: 39232499 DOI: 10.1016/j.chembiol.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 05/21/2024] [Accepted: 08/05/2024] [Indexed: 09/06/2024]
Abstract
Paclitaxel-resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Here, using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. In addition, type I PRMT inhibition synergies with PRMT5 inhibition in suppressing tumor growth of drug-resistant cells through augmenting perturbation of AURKB-mediated mitotic signaling pathway. These findings are fully recapitulated in a patient-derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.
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Affiliation(s)
- KeJing Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China; Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan 410000, China
| | - Juan Wei
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - SheYu Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Liyan Fei
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Lu Guo
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Xueying Liu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - YiShuai Ji
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - WenJun Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Felipe E Ciamponi
- Molecular Biology and Genetic Engineering Center (CBMEG), Medicinal Chemistry Center (CQMED), Structural Genomics Consortium (SGC-UNICAMP), University of Campinas-UNICAMP, Campinas 13083-872, Brazil
| | - WeiChang Chen
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - MengXi Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410083, China; Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan 410000, China
| | - Jie Zhai
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Ting Fu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Katlin B Massirer
- Molecular Biology and Genetic Engineering Center (CBMEG), Medicinal Chemistry Center (CQMED), Structural Genomics Consortium (SGC-UNICAMP), University of Campinas-UNICAMP, Campinas 13083-872, Brazil
| | - Yang Yu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Mathieu Lupien
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada; Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
| | - Yong Wei
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
| | - Cheryl H Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada.
| | - Qin Wu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
| | - WeiHong Tan
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.
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Jiang L, Kong F, Yao L, Zhang F, Wu L, Zhang H, Yang G, Wang S, Jin X, Wang X, Tong X, Zhang S. Successful intracytoplasmic sperm injection in a macrozoospermia case with novel compound heterozygous aurora kinase C (AURKC) mutations. Arch Gynecol Obstet 2024; 310:2211-2221. [PMID: 39133293 DOI: 10.1007/s00404-024-07619-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 06/18/2024] [Indexed: 08/13/2024]
Abstract
PURPOSE To explore the application possibility of macrocephalic sperm from a patient with 100% macrocephalic sperm and AURKC gene variations. METHODS We diagnosed a case of macrozoospermia with 100% macrocephalic sperm and 39.5% multi-tailed spermatozoa by morphological analysis. Whole-exome sequencing (WES) was used for the patient and his wife. Sanger sequencing technique was used to verify the AURKC mutations in the patient's parents and his offspring. Sperm's ploidy was tested by flow cytometry. The couple asked for intra-couple ART therapy. RESULTS The patient presented novel compound heterozygous AURKC mutations (c.434C > T, c.497A > T) by WES. Sanger sequencing validation showed that variant of c.434C > T was observed in his father and c.497A > T was observed in his mother. Flow cytometry revealed that there existed a certain proportion of haploid sperm. Macrocephalic spermatozoa whose heads were smaller than the diameter of injection needle were selected for microinjection. A singleton pregnancy was achieved after embryo transfer. Prenatal diagnosis revealed that the fetus had normal chromosomal karyotype. Sanger sequencing technique showed that the fetus carried a c.434C > T mutation in one AURKC allele. A 3730 g healthy male fetus was delivered at term. CONCLUSION Our study reported a successful live birth from a patient with definite AURKC gene variants and may provide insights for such patients to choose donor sperm or their own sperm.
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Affiliation(s)
- Lingying Jiang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Feifei Kong
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Lv Yao
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Fuxing Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Lingfeng Wu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Haocheng Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Guobing Yang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Shasha Wang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Xiaoying Jin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Xiufen Wang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China
| | - Xiaomei Tong
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China.
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, Zhejiang, China.
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3rd Qingchun East Road, Hangzhou, Zhejiang, China.
- Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, Zhejiang, China.
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Rajesh R U, Sangeetha D. Therapeutic potentials and targeting strategies of quercetin on cancer cells: Challenges and future prospects. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 133:155902. [PMID: 39059266 DOI: 10.1016/j.phymed.2024.155902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/08/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND Every cell in the human body is vital because it maintains equilibrium and carries out a variety of tasks, including growth and development. These activities are carried out by a set of instructions carried by many different genes and organized into DNA. It is well recognized that some lifestyle decisions, like using tobacco, alcohol, UV, or multiple sexual partners, might increase one's risk of developing cancer. The advantages of natural products for any health issue are well known, and researchers are making attempts to separate flavonoid-containing substances from plants. Various parts of plants contain a phenolic compound called flavonoid. Quercetin, which belongs to the class of compounds known as flavones with chromone skeletal structure, has anti-cancer activity. PURPOSE The study was aimed at investigating the therapeutic action of the flavonoid quercetin on various cancer cells. METHODS The phrases quercetin, anti-cancer, nanoparticles, and cell line were used to search the data using online resources such as PubMed, and Google Scholar. Several critical previous studies have been included. RESULTS Quercetin inhibits various dysregulated signaling pathways that cause cancer cells to undergo apoptosis to exercise its anticancer effects. Numerous signaling pathways are impacted by quercetin, such as the Hedgehog system, Akt, NF-κB pathway, downregulated mutant p53, JAK/STAT, G1 phase arrest, Wnt/β-Catenin, and MAPK. There are downsides to quercetin, like hydrophobicity, first-pass effect, instability in the gastrointestinal tract, etc., because of which it is not well-established in the pharmaceutical industry. The solution to these drawbacks in the future is using bio-nanomaterials like chitosan, PLGA, liposomes, and silk fibroin as carriers, which can enhance the target specificity of quercetin. The first section of this review covers the specifics of flavonoids and quercetin; the second section covers the anti-cancer activity of quercetin; and the third section explains the drawbacks and conjugation of quercetin with nanoparticles for drug delivery by overcoming quercetin's drawback. CONCLUSIONS Overall, this review presented details about quercetin, which is a plant derivative with a promising molecular mechanism of action. They inhibit cancer by various mechanisms with little or no side effects. It is anticipated that plant-based materials will become increasingly relevant in the treatment of cancer.
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Affiliation(s)
- Udaya Rajesh R
- Department of Chemistry, School of Advanced Science, Vellore Institute of Technology, Vellore, 632014 Tamil Nadu, India
| | - Dhanaraj Sangeetha
- Department of Chemistry, School of Advanced Science, Vellore Institute of Technology, Vellore, 632014 Tamil Nadu, India.
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Nikhil K, Shah K. The significant others of aurora kinase a in cancer: combination is the key. Biomark Res 2024; 12:109. [PMID: 39334449 PMCID: PMC11438406 DOI: 10.1186/s40364-024-00651-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
AURKA is predominantly famous as an essential mitotic kinase. Recent findings have also established its critical role in a plethora of other biological processes including ciliogenesis, mitochondrial dynamics, neuronal outgrowth, DNA replication and cell cycle progression. AURKA overexpression in numerous cancers is strongly associated with poor prognosis and survival. Still no AURKA-targeted drug has been approved yet, partially because of the associated collateral toxicity and partly due to its limited efficacy as a single agent in a wide range of tumors. Mechanistically, AURKA overexpression allows it to phosphorylate numerous pathological substrates promoting highly aggressive oncogenic phenotypes. Our review examines the most recent advances in AURKA regulation and focuses on 33 such direct cancer-specific targets of AURKA and their associated oncogenic signaling cascades. One of the common themes that emerge is that AURKA is often involved in a feedback loop with its substrates, which could be the decisive factor causing its sustained upregulation and hyperactivation in cancer cells, an Achilles heel not exploited before. This dynamic interplay between AURKA and its substrates offers potential opportunities for targeted therapeutic interventions. By targeting these substrates, it may be possible to disrupt this feedback loop to effectively reverse AURKA levels, thereby providing a promising avenue for developing safer AURKA-targeted therapeutics. Additionally, exploring the synergistic effects of AURKA inhibition with its other oncogenic and/or tumor-suppressor targets could provide further opportunities for developing effective combination therapies against AURKA-driven cancers, thereby maximizing its potential as a critical drug target.
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Affiliation(s)
- Kumar Nikhil
- Department of Chemistry, Purdue University Institute for Cancer Research, 560 Oval Drive, West Lafayette, IN, 47907, USA.
- School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, 751024, India.
| | - Kavita Shah
- Department of Chemistry, Purdue University Institute for Cancer Research, 560 Oval Drive, West Lafayette, IN, 47907, USA.
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Graziani A, Rocca MS, Vinanzi C, Masi G, Grande G, De Toni L, Ferlin A. Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence. Genes (Basel) 2024; 15:600. [PMID: 38790229 PMCID: PMC11120687 DOI: 10.3390/genes15050600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/26/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Several genes are implicated in spermatogenesis and fertility regulation, and these genes are presently being analysed in clinical practice due to their involvement in male factor infertility (MFI). However, there are still few genetic analyses that are currently recommended for use in clinical practice. In this manuscript, we reviewed the genetic causes of qualitative sperm defects. We distinguished between alterations causing reduced sperm motility (asthenozoospermia) and alterations causing changes in the typical morphology of sperm (teratozoospermia). In detail, the genetic causes of reduced sperm motility may be found in the alteration of genes associated with sperm mitochondrial DNA, mitochondrial proteins, ion transport and channels, and flagellar proteins. On the other hand, the genetic causes of changes in typical sperm morphology are related to conditions with a strong genetic basis, such as macrozoospermia, globozoospermia, and acephalic spermatozoa syndrome. We tried to distinguish alterations approved for routine clinical application from those still unsupported by adequate clinical studies. The most important aspect of the study was related to the correct identification of subjects to be tested and the correct application of genetic tests based on clear clinical data. The correct application of available genetic tests in a scenario where reduced sperm motility and changes in sperm morphology have been observed enables the delivery of a defined diagnosis and plays an important role in clinical decision-making. Finally, clarifying the genetic causes of MFI might, in future, contribute to reducing the proportion of so-called idiopathic MFI, which might indeed be defined as a subtype of MFI whose cause has not yet been revealed.
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Affiliation(s)
- Andrea Graziani
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
| | - Maria Santa Rocca
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
| | - Cinzia Vinanzi
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
| | - Giulia Masi
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
| | - Giuseppe Grande
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
| | - Luca De Toni
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
| | - Alberto Ferlin
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
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10
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Andrade AAR, Pauli F, Pressete CG, Zavan B, Hanemann JAC, Miyazawa M, Fonseca R, Caixeta ES, Nacif JLM, Aissa AF, Barreiro EJ, Ionta M. Antiproliferative Activity of N-Acylhydrazone Derivative on Hepatocellular Carcinoma Cells Involves Transcriptional Regulation of Genes Required for G2/M Transition. Biomedicines 2024; 12:892. [PMID: 38672246 PMCID: PMC11048582 DOI: 10.3390/biomedicines12040892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 04/07/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Liver cancer is the second leading cause of cancer-related death in males. It is estimated that approximately one million deaths will occur by 2030 due to hepatic cancer. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer subtype and is commonly diagnosed at an advanced stage. The drug arsenal used in systemic therapy for HCC is very limited. Multikinase inhibitors sorafenib (Nexavar®) and lenvatinib (Lenvima®) have been used as first-line drugs with modest therapeutic effects. In this scenario, it is imperative to search for new therapeutic strategies for HCC. Herein, the antiproliferative activity of N-acylhydrazone derivatives was evaluated on HCC cells (HepG2 and Hep3B), which were chemically planned on the ALL-993 scaffold, a potent inhibitor of vascular endothelial growth factor 2 (VEGFR2). The substances efficiently reduced the viability of HCC cells, and the LASSBio-2052 derivative was the most effective. Further, we demonstrated that LASSBio-2052 treatment induced FOXM1 downregulation, which compromises the transcriptional activation of genes required for G2/M transition, such as AURKA and AURKB, PLK1, and CDK1. In addition, LASSBio-2052 significantly reduced CCNB1 and CCND1 expression in HCC cells. Our findings indicate that LASSBio-2052 is a promising prototype for further in vivo studies.
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Affiliation(s)
| | - Fernanda Pauli
- Institute of Chemistry, Fluminense Federal University, Niterói 24020-140, RJ, Brazil
| | - Carolina Girotto Pressete
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil (A.F.A.)
| | - Bruno Zavan
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil (A.F.A.)
| | | | - Marta Miyazawa
- School of Dentistry, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil
| | - Rafael Fonseca
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil (A.F.A.)
| | - Ester Siqueira Caixeta
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil (A.F.A.)
| | | | - Alexandre Ferro Aissa
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil (A.F.A.)
| | - Eliezer J. Barreiro
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro 21941-914, RJ, Brazil
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas, Alfenas 37130-001, MG, Brazil (A.F.A.)
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11
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Tian YY, Tong JB, Liu Y, Tian Y. QSAR Study, Molecular Docking and Molecular Dynamic Simulation of Aurora Kinase Inhibitors Derived from Imidazo[4,5- b]pyridine Derivatives. Molecules 2024; 29:1772. [PMID: 38675594 PMCID: PMC11052498 DOI: 10.3390/molecules29081772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024] Open
Abstract
Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules.
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Affiliation(s)
- Yang-Yang Tian
- College of Petroleum Engineering, Xi’an Shiyou University, Xi’an 710065, China;
- Shaanxi Key Laboratory of Advanced Stimulation Technology for Oil & Gas Reservoirs, Xi’an 710065, China
| | - Jian-Bo Tong
- College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (Y.L.); (Y.T.)
| | - Yuan Liu
- College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (Y.L.); (Y.T.)
| | - Yu Tian
- College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China; (Y.L.); (Y.T.)
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12
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Kamboj P, Mahore A, Husain A, Amir M. Benzothiazole-based apoptosis inducers: A comprehensive overview and future prospective. Arch Pharm (Weinheim) 2024; 357:e2300493. [PMID: 38212254 DOI: 10.1002/ardp.202300493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/24/2023] [Accepted: 12/06/2023] [Indexed: 01/13/2024]
Abstract
Cancer has become a major concern in healthcare globally, and over time, incidences and prevalence of cancer are increasing. To counter this, a lot of anticancer drugs are approved and are in clinical use, playing a pivotal role in its treatment. Due to drug resistance and adverse effects, a continuous demand for novel, potent, and safe candidates to treat cancer is always there. Over the last few decades, various heterocyclic ring-based derivatives have been explored and reported in the literature. In this regard, benzothiazole scaffold-based compound emerged as the versatile ring for developing novel and safe anticancer candidates. In this article, we have reported various benzothiazole heterocyclic ring-based derivatives demonstrating potent antiproliferative activity by induction of apoptosis via an intrinsic pathway in a dose-dependent manner. These compounds also displayed inhibition of different enzymes, for example, Aurora kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, phosphoinositide kinases, DNA topoisomerase, and tubulin polymerases. This study focused on a comprehensive overview of antiproliferative activity, structure-activity relationship, apoptosis induction activity, and enzyme inhibition by benzothiazole-based compounds.
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Affiliation(s)
- Payal Kamboj
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
| | - Anjali Mahore
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
| | - Asif Husain
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
| | - Mohammad Amir
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, India
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13
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Helmy SWA, Abdel-Aziz AK, Dokla EME, Ahmed TE, Hatem Y, Abdel Rahman EA, Sharaky M, Shahin MI, Elrazaz EZ, Serya RAT, Henary M, Ali SS, Abou El Ella DA. Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells. Eur J Med Chem 2024; 268:116255. [PMID: 38401190 DOI: 10.1016/j.ejmech.2024.116255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/07/2024] [Accepted: 02/16/2024] [Indexed: 02/26/2024]
Abstract
Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases' aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC. Based on a previously reported indolinone-based Aurora B kinase inhibitor (III), and guided by structural modification and SAR investigation, we initially synthesized 11 sulfonamide-indolinone hybrids (5a-k), which showed differential antiproliferative activities against the NCI-60 cell line panel with BC cells displaying preferential sensitivity. Nonetheless, modest activity against Aurora B kinase (18-49% inhibition) was noted at 100 nM. Screening of a representative derivative (5d) against 17 kinases, which are overexpressed in BC, failed to show significant activity at 1 μM concentration, suggesting that kinase inhibitory activity only played a partial role in targeting BC. Bioinformatic analyses of genome-wide transcriptomics (RNA-sequencing), metabolomics, and CRISPR loss-of-function screens datasets suggested that indolinone-completely responsive BC cell lines (MCF7, MDA-MB-468, and T-47D) were more dependent on mitochondrial oxidative phosphorylation (OXPHOS) compared to partially responsive BC cell lines (MDA-MB-231, BT-549, and HS 578 T). An optimized derivative, TC11, obtained by molecular hybridization of 5d with sunitinib polar tail, manifested superior antiproliferative activity and was used for further investigations. Indeed, TC11 significantly reduced/impaired the mitochondrial respiration, as well as mitochondria-dependent ROS production of MCF7 cells. Furthermore, TC11 induced G0/G1 cell cycle arrest and apoptosis of MCF7 BC cells. Notably, anticancer doses of TC11 did not elicit cytotoxic effects on normal cardiomyoblasts and hepatocytes. Altogether, these findings emphasize the therapeutic potential of targeting the metabolic vulnerability of OXPHOS-dependent BC cells using TC11 and its related sulfonamide-indolinone hybrids. Further investigation is warranted to identify their precise/exact molecular target.
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Affiliation(s)
- Sama W A Helmy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt
| | - Amal Kamal Abdel-Aziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt; Smart Health Initiative, Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia
| | - Eman M E Dokla
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
| | - Tarek E Ahmed
- Department of Chemistry and Center of Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue SE, Atlanta, GA, 30303, USA
| | - Yasmin Hatem
- Research Department, 57357 Children's Cancer Hospital Egypt, Cairo, 4260102, Egypt
| | - Engy A Abdel Rahman
- Research Department, 57357 Children's Cancer Hospital Egypt, Cairo, 4260102, Egypt; Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Marwa Sharaky
- Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, 11796, Egypt
| | - Mai I Shahin
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt
| | - Eman Z Elrazaz
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt
| | - Rabah A T Serya
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt
| | - Maged Henary
- Department of Chemistry and Center of Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue SE, Atlanta, GA, 30303, USA
| | - Sameh S Ali
- Research Department, 57357 Children's Cancer Hospital Egypt, Cairo, 4260102, Egypt
| | - Dalal A Abou El Ella
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
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14
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Melo ML, Fonseca R, Pauli F, Zavan B, Hanemann JAC, Miyazawa M, Caixeta ES, Nacif JLM, Aissa AF, Barreiro EJ, Ionta M. N-acylhydrazone derivative modulates cell cycle regulators promoting mitosis arrest and apoptosis in estrogen positive MCF-7 breast cancer cells. Toxicol In Vitro 2023; 93:105686. [PMID: 37652252 DOI: 10.1016/j.tiv.2023.105686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/14/2023] [Accepted: 08/28/2023] [Indexed: 09/02/2023]
Abstract
Breast cancer is the leading cause of cancer death among women worldwide. About 75% of all diagnosed cases are hormone-positive, which are treated with hormone therapy. However, many patients are refractory or become resistant to the drugs used in therapeutic protocols. In this scenario, it is essential to identify new substances with pharmacological potential against breast cancer. VEGFR2 inhibitors are considered promising antitumor agents not only due to their antiangiogenic activity but also by inhibiting the proliferation of tumor cells. Thus, the present study aimed to evaluate the effects of N-acylhydrazone derivative LASSBio-2029 on the proliferative behavior of MCF-7 cells. We observed a promising antitumor potential of this substance due to its ability to modulate critical cell cycle regulators including mitotic kinases (CDK1, AURKA, AURKB, and PLK1) and CDK inhibitor (CDKN1A). Increased frequencies of abnormal mitosis and apoptotic cells were observed in response to treatment. A molecular docking analysis predicts that LASSBio-2029 could bind to the proto-oncoprotein ABL1, which participates in cell cycle control, interacting with other controller proteins and regulating centrosome-associated tubulins. Finally, we created a gene signature with the downregulated genes, whose reduced expression is associated with a higher relapse-free survival probability in breast cancer patients.
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Affiliation(s)
- Melissa Lúcia Melo
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil
| | - Rafael Fonseca
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil
| | - Fernanda Pauli
- Institute of Chemistry, Fluminense Federal University, Niterói, RJ 24020-140, Brazil
| | - Bruno Zavan
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil
| | - João Adolfo Costa Hanemann
- Department of Clinic and Surgery, School of Dentistry. Federal University of Alfenas, 37130-001, MG, Brazil
| | - Marta Miyazawa
- Department of Clinic and Surgery, School of Dentistry. Federal University of Alfenas, 37130-001, MG, Brazil
| | | | | | - Alexandre Ferro Aissa
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil.
| | - Eliezer J Barreiro
- Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro, CCS, Rio de Janeiro, RJ, Brazil.
| | - Marisa Ionta
- Institute of Biomedical Sciences, Federal University of Alfenas, MG 37130-001, Brazil.
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15
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Gambelli A, Ferrando A, Boncristiani C, Schoeftner S. Regulation and function of R-loops at repetitive elements. Biochimie 2023; 214:141-155. [PMID: 37619810 DOI: 10.1016/j.biochi.2023.08.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 08/13/2023] [Accepted: 08/19/2023] [Indexed: 08/26/2023]
Abstract
R-loops are atypical, three-stranded nucleic acid structures that contain a stretch of RNA:DNA hybrids and an unpaired, single stranded DNA loop. R-loops are physiological relevant and can act as regulators of gene expression, chromatin structure, DNA damage repair and DNA replication. However, unscheduled and persistent R-loops are mutagenic and can mediate replication-transcription conflicts, leading to DNA damage and genome instability if left unchecked. Detailed transcriptome analysis unveiled that 85% of the human genome, including repetitive regions, hold transcriptional activity. This anticipates that R-loops management plays a central role for the regulation and integrity of genomes. This function is expected to have a particular relevance for repetitive sequences that make up to 75% of the human genome. Here, we review the impact of R-loops on the function and stability of repetitive regions such as centromeres, telomeres, rDNA arrays, transposable elements and triplet repeat expansions and discuss their relevance for associated pathological conditions.
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Affiliation(s)
- Alice Gambelli
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy
| | - Alessandro Ferrando
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy
| | - Chiara Boncristiani
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy
| | - Stefan Schoeftner
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Via E. Weiss 2, 34127, Trieste, Italy.
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16
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Ren B, Geng Y, Chen S, Gao Z, Zheng K, Yang Y, Luo Q, Feng J, Luo Z, Ju Y, Huang Z. Alisertib exerts KRAS allele‑specific anticancer effects on colorectal cancer cell lines. Exp Ther Med 2023; 25:243. [PMID: 37153900 PMCID: PMC10160916 DOI: 10.3892/etm.2023.11942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 02/27/2023] [Indexed: 05/10/2023] Open
Abstract
The aim of the present study was to examine the effects of alisertib (ALS) on RAS signaling pathways against a panel of colorectal cancer (CRC) cell lines and engineered Flp-In stable cell lines expressing different Kirsten rat sarcoma virus (KRAS) mutants. The viability of Caco-2KRAS wild-type, Colo-678KRAS G12D, SK-CO-1KRAS G12V, HCT116KRAS G13D, CCCL-18KRAS A146T and HT29BRAF V600E cells was examined by Cell Titer-Glo assay, and that of stable cell lines was monitored by IncuCyte. The expression levels of phosphorylated (p-)Akt and p-Erk as RAS signal outputs were measured by western blotting. The results suggested that ALS exhibited different inhibitory effects on cell viability and different regulatory effects on guanosine triphosphate (GTP)-bound RAS in CRC cell lines. ALS also exhibited various regulatory effects on the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways, the two dominant RAS signaling pathways, and induced apoptosis and autophagy in a RAS allele-specific manner. Combined treatment with ALS and selumetinib enhanced the regulatory effects of ALS on apoptosis and autophagy in CRC cell lines in a RAS allele-specific manner. Notably, combined treatment exhibited a synergistic inhibitory effect on cell proliferation in Flp-In stable cell lines. The results of the present study suggested that ALS differentially regulates RAS signaling pathways. The combined approach of ALS and a MEK inhibitor may represent a new therapeutic strategy for precision therapy for CRC in a KRAS allele-specific manner; however, this effect requires further study in vivo.
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Affiliation(s)
- Baojun Ren
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
| | - Yan Geng
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
| | - Shuxiang Chen
- Department of Anesthesiology and Operating Theatre, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
| | - Zhuowei Gao
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
| | - Kehong Zheng
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Yong Yang
- Department of Gastrointestinal Surgery, Peking University Shougang Hospital, Beijing 100144, P.R. China
| | - Qimei Luo
- Department of Nephrology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
| | - Jing Feng
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
| | - Zhentao Luo
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
| | - Yongle Ju
- Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, Foshan, Guangdong 528308, P.R. China
- Correspondence to: Dr Yongle Ju, Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, 1 Jiazi Road, Lunjiao Shunde, Foshan, Guangdong 528308, P.R. China
| | - Zonghai Huang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
- Correspondence to: Dr Yongle Ju, Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), The Second School of Clinical Medicine, Southern Medical University, 1 Jiazi Road, Lunjiao Shunde, Foshan, Guangdong 528308, P.R. China
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17
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Kovacs AH, Zhao D, Hou J. Aurora B Inhibitors as Cancer Therapeutics. Molecules 2023; 28:3385. [PMID: 37110619 PMCID: PMC10144992 DOI: 10.3390/molecules28083385] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/29/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
The Aurora kinases (A, B, and C) are a family of three isoform serine/threonine kinases that regulate mitosis and meiosis. The Chromosomal Passenger Complex (CPC), which contains Aurora B as an enzymatic component, plays a critical role in cell division. Aurora B in the CPC ensures faithful chromosome segregation and promotes the correct biorientation of chromosomes on the mitotic spindle. Aurora B overexpression has been observed in several human cancers and has been associated with a poor prognosis for cancer patients. Targeting Aurora B with inhibitors is a promising therapeutic strategy for cancer treatment. In the past decade, Aurora B inhibitors have been extensively pursued in both academia and industry. This paper presents a comprehensive review of the preclinical and clinical candidates of Aurora B inhibitors as potential anticancer drugs. The recent advances in the field of Aurora B inhibitor development will be highlighted, and the binding interactions between Aurora B and inhibitors based on crystal structures will be presented and discussed to provide insights for the future design of more selective Aurora B inhibitors.
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Affiliation(s)
- Antal H. Kovacs
- Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
| | - Dong Zhao
- Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
| | - Jinqiang Hou
- Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
- Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada
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18
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Xu S, Liu D, Cui M, Zhang Y, Zhang Y, Guo S, Zhang H. Identification of Hub Genes for Early Diagnosis and Predicting Prognosis in Colon Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1893351. [PMID: 35774271 PMCID: PMC9239823 DOI: 10.1155/2022/1893351] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/01/2022] [Indexed: 02/07/2023]
Abstract
Colon adenocarcinoma (COAD) is among the most common digestive system malignancies worldwide, and its pathogenesis and gene signatures remain unclear. This study explored the genetic characteristics and molecular mechanisms underlying colon cancer development. Three gene expression data sets were obtained from the Gene Expression Omnibus (GEO) database. GEO2R was used to determine differentially expressed genes (DEGs) between COAD and normal tissues. Then, the intersection of the data sets was obtained. Metascape was used to perform the functional enrichment analyses. Next, STRING was used to build protein-protein interaction (PPI) networks. Hub genes were identified and analysed using Cytoscape. Next, survival analysis and expression analysis of the hub genes were performed. ROC curve analysis was performed for further test of the diagnostic efficacy. Finally, alterations in the hub genes were predicted and analysed by cBioPortal. Altogether, 436 DEGs were detected. The DEGs were mainly enriched in cell cycle phase transition, nuclear division, meiotic nuclear division, and cytokinesis. Based on PPI networks, 20 hub genes were selected. Among them, 6 hub genes (CCNB1, CCNA2, AURKA, NCAPG, DLGAP5, and CENPE) showed significant prognostic value in colon cancer (P < 0.05), while 5 hub genes (CDK1, CCNB1, CCNA2, MAD2L1, and DLGAP5) were associated with early colon cancer diagnosis and ROC curve analysis showed good diagnostic accuracy. In conclusion, integrated bioinformatics analysis was used to identify hub genes that reveal the potential mechanism of carcinogenesis and progression of colon cancer. The hub genes might be novel biomarkers for early diagnosis, treatment, and prognosis of colon cancer.
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Affiliation(s)
- Shuo Xu
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China
| | - Dingsheng Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China
| | - Mingming Cui
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China
| | - Yao Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China
| | - Yu Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China
| | - Shiqi Guo
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China
| | - Hong Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, China
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19
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Nardou K, Nicolas M, Kuttler F, Cisarova K, Celik E, Quinodoz M, Riggi N, Michielin O, Rivolta C, Turcatti G, Moulin AP. Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening. Cancers (Basel) 2022; 14:cancers14061575. [PMID: 35326726 PMCID: PMC8946509 DOI: 10.3390/cancers14061575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 02/05/2023] Open
Abstract
Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor.
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Affiliation(s)
- Katya Nardou
- Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland; (K.N.); (M.N.)
| | - Michael Nicolas
- Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland; (K.N.); (M.N.)
| | - Fabien Kuttler
- Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; (F.K.); (G.T.)
| | - Katarina Cisarova
- Medical Genetics Unit, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland;
| | - Elifnaz Celik
- Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; (E.C.); (M.Q.); (C.R.)
- Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland
| | - Mathieu Quinodoz
- Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; (E.C.); (M.Q.); (C.R.)
- Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Nicolo Riggi
- Experimental Pathology, Institute of Pathology, Lausanne University, 1011 Lausanne, Switzerland;
| | - Olivier Michielin
- Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland;
| | - Carlo Rivolta
- Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; (E.C.); (M.Q.); (C.R.)
- Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Gerardo Turcatti
- Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; (F.K.); (G.T.)
| | - Alexandre Pierre Moulin
- Jules-Gonin Eye Hospital, University of Lausanne, 1004 Lausanne, Switzerland; (K.N.); (M.N.)
- Correspondence:
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20
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Zhou X, Mould DR, Yuan Y, Fox E, Greengard E, Faller DV, Venkatakrishnan K. Population Pharmacokinetics and Exposure-Safety Relationships of Alisertib in Children and Adolescents With Advanced Malignancies. J Clin Pharmacol 2022; 62:206-219. [PMID: 34435684 PMCID: PMC9274904 DOI: 10.1002/jcph.1958] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 08/22/2021] [Indexed: 11/10/2022]
Abstract
Population pharmacokinetic (PK) and exposure-safety analyses of alisertib were performed in children enrolled in 2 clinical trials: NCT02444884 and NCT01154816. NCT02444884 was a dose-finding study in children with relapsed/refractory solid malignancies (phase 1) or neuroblastomas (phase 2). Patients received oral alisertib 45 to 100 mg/m2 as powder-in-capsule once daily or twice daily for 7 days in 21-day cycles. Serial blood samples were collected up to 24 hours after dosing on cycle 1, day 1. NCT01154816 was a phase 2 single-arm study evaluating efficacy in children with relapsed/refractory solid malignancies or acute leukemias. Patients received alisertib 80 mg/m2 as enteric-coated tablets once daily for 7 days in 21-day cycles. Sparse PK samples were collected up to 8 hours after dosing on cycle 1, day 1. Sources of alisertib PK variability were characterized and quantified using nonlinear mixed-effects modeling to support dosing recommendations in children and adolescents. A 2-compartment model with oral absorption described by 3 transit compartments was developed using data from 146 patients. Apparent oral clearance and central distribution volume were correlated with body surface area across the age range of 2 to 21 years, supporting the use of body surface area-based alisertib dosing in the pediatric population. The recommended dose of 80 mg/m2 once daily enteric-coated tablets provided similar alisertib exposures across pediatric age groups and comparable exposure to that in adults receiving 50 mg twice daily (recommended adult dose). Statistically significant relationships (P < .01) were observed between alisertib exposures and incidence of grade ≥2 stomatitis and febrile neutropenia, consistent with antiproliferative mechanism-related toxicities.
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Affiliation(s)
- Xiaofei Zhou
- Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USAa wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | | | - Ying Yuan
- Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USAa wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Elizabeth Fox
- St. Jude Children's Research HospitalMemphisTennesseeUSA
| | | | - Douglas V. Faller
- Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USAa wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Karthik Venkatakrishnan
- Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts, USAa wholly owned subsidiary of Takeda Pharmaceutical Company Limited
- Current affiliation: EMD Serono IncBillericaMassachusettsUSA
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21
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Gupta D, Kumar M, Singh M, Salman M, Das U, Kaur P. Identification of polypharmacological anticancerous molecules against Aurora kinase family of proteins. J Cell Biochem 2022; 123:719-735. [PMID: 35040172 DOI: 10.1002/jcb.30214] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/27/2021] [Accepted: 12/30/2021] [Indexed: 12/28/2022]
Abstract
The Human Aurora Kinase (AURK) protein family is the key player of cell cycle events including spindle assembly, kinetochore formation, chromosomal segregation, centrosome separation, microtubule dynamics, and cytokinesis. Their aberrant expression has been extensively linked with chromosomal instability in addition to derangement of multiple tumor suppressors and oncoprotein regulated pathways. Therefore, the AURK family of kinases is a promising target for the treatment of various types of cancer. Over the past few decades, several potential inhibitors of AURK proteins have been identified and have reached various phases of clinical trials. But very few molecules have currently crossed the safety criteria due to their various toxic side effects. In the present study, we have adopted a computational polypharmacological strategy and identified four novel molecules that can target all three AURKs. These molecules were further investigated for their binding stabilities at the ATP binding pocket using molecular dynamics based simulation studies. The molecules selected adopting a multipronged computational approach can be considered as potential AURKs inhibitors for cancer therapeutics.
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Affiliation(s)
- Deepali Gupta
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Mukesh Kumar
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Mandeep Singh
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Mohd Salman
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Uddipan Das
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
| | - Punit Kaur
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
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22
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Baltzer S, Bulatov T, Schmied C, Krämer A, Berger BT, Oder A, Walker-Gray R, Kuschke C, Zühlke K, Eichhorst J, Lehmann M, Knapp S, Weston J, von Kries JP, Süssmuth RD, Klussmann E. Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells. Int J Mol Sci 2022; 23:ijms23020763. [PMID: 35054947 PMCID: PMC8776063 DOI: 10.3390/ijms23020763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/30/2021] [Accepted: 01/08/2022] [Indexed: 02/01/2023] Open
Abstract
The cAMP-dependent aquaporin-2 (AQP2) redistribution from intracellular vesicles into the plasma membrane of renal collecting duct principal cells induces water reabsorption and fine-tunes body water homeostasis. However, the mechanisms controlling the localization of AQP2 are not understood in detail. Using immortalized mouse medullary collecting duct (MCD4) and primary rat inner medullary collecting duct (IMCD) cells as model systems, we here discovered a key regulatory role of Aurora kinase A (AURKA) in the control of AQP2. The AURKA-selective inhibitor Aurora-A inhibitor I and novel derivatives as well as a structurally different inhibitor, Alisertib, prevented the cAMP-induced redistribution of AQP2. Aurora-A inhibitor I led to a depolymerization of actin stress fibers, which serve as tracks for the translocation of AQP2-bearing vesicles to the plasma membrane. The phosphorylation of cofilin-1 (CFL1) inactivates the actin-depolymerizing function of CFL1. Aurora-A inhibitor I decreased the CFL1 phosphorylation, accounting for the removal of the actin stress fibers and the inhibition of the redistribution of AQP2. Surprisingly, Alisertib caused an increase in actin stress fibers and did not affect CFL1 phosphorylation, indicating that AURKA exerts its control over AQP2 through different mechanisms. An involvement of AURKA and CFL1 in the control of the localization of AQP2 was hitherto unknown.
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Affiliation(s)
- Sandrine Baltzer
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (S.B.); (R.W.-G.); (C.K.); (K.Z.)
- Institute of Chemistry, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany; (T.B.); (R.D.S.)
| | - Timur Bulatov
- Institute of Chemistry, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany; (T.B.); (R.D.S.)
| | - Christopher Schmied
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (C.S.); (A.O.); (J.E.); (M.L.); (J.P.v.K.)
| | - Andreas Krämer
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany; (A.K.); (B.-T.B.); (S.K.)
- Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany
- DKTK (German Translational Research Network), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany
| | - Benedict-Tilman Berger
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany; (A.K.); (B.-T.B.); (S.K.)
- Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany
| | - Andreas Oder
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (C.S.); (A.O.); (J.E.); (M.L.); (J.P.v.K.)
| | - Ryan Walker-Gray
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (S.B.); (R.W.-G.); (C.K.); (K.Z.)
| | - Christin Kuschke
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (S.B.); (R.W.-G.); (C.K.); (K.Z.)
| | - Kerstin Zühlke
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (S.B.); (R.W.-G.); (C.K.); (K.Z.)
| | - Jenny Eichhorst
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (C.S.); (A.O.); (J.E.); (M.L.); (J.P.v.K.)
| | - Martin Lehmann
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (C.S.); (A.O.); (J.E.); (M.L.); (J.P.v.K.)
| | - Stefan Knapp
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany; (A.K.); (B.-T.B.); (S.K.)
- Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany
- DKTK (German Translational Research Network), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany
- Frankfurt Cancer Institute, 60596 Frankfurt am Main, Germany
| | - John Weston
- JQuest Consulting, Carl-Orff-Weg 25, 65779 Kelkheim, Germany;
| | - Jens Peter von Kries
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (C.S.); (A.O.); (J.E.); (M.L.); (J.P.v.K.)
| | - Roderich D. Süssmuth
- Institute of Chemistry, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany; (T.B.); (R.D.S.)
| | - Enno Klussmann
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany; (S.B.); (R.W.-G.); (C.K.); (K.Z.)
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany
- Correspondence: ; Tel.: +49-30-9406-2596
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23
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Yao F, Zhan Y, Li C, Lu Y, Chen J, Deng J, Wu Z, Li Q, Song Y, Chen B, Chen J, Tian K, Pu Z, Ni Y, Mou L. Single-Cell RNA Sequencing Reveals the Role of Phosphorylation-Related Genes in Hepatocellular Carcinoma Stem Cells. Front Cell Dev Biol 2022; 9:734287. [PMID: 35059393 PMCID: PMC8763978 DOI: 10.3389/fcell.2021.734287] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 12/08/2021] [Indexed: 01/05/2023] Open
Abstract
Abnormal activation of protein kinases and phosphatases is implicated in various tumorigenesis, including hepatocellular carcinoma (HCC). Advanced HCC patients are treated with systemic therapy, including tyrosine kinase inhibitors, which extend overall survival. Investigation of the underlying mechanism of protein kinase signaling will help to improve the efficacy of HCC therapy. Combining single-cell RNA sequencing data and TCGA RNA-seq data, we profiled the protein kinases, phosphatases, and other phosphorylation-related genes (PRGs) of HCC patients in this study. We found nine protein kinases and PRGs with high expression levels that were mainly detected in HCC cancer stem cells, including POLR2G, PPP2R1A, POLR2L, PRC1, ITBG1BP1, MARCKSL1, EZH2, DTYMK, and AURKA. Survival analysis with the TCGA dataset showed that these genes were associated with poor prognosis of HCC patients. Further correlation analysis showed that these genes were involved in cell cycle-related pathways that may contribute to the development of HCC. Among them, AURKA and EZH2 were identified as two hub genes by Ingenuity Pathway Analysis. Treatment with an AURKA inhibitor (alisertib) and an EZH2 inhibitor (gambogenic) inhibited HCC cell proliferation, migration, and invasion. We also found that both AURKA and EZH2 were highly expressed in TP53-mutant HCC samples. Our comprehensive analysis of PRGs contributes to illustrating the mechanisms underlying HCC progression and identifying potential therapeutic targets for future clinical trials.
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Affiliation(s)
- Fuwen Yao
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yongqiang Zhan
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Changzheng Li
- Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Ying Lu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jiao Chen
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jing Deng
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Zijing Wu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Qi Li
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yi’an Song
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Binhua Chen
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jinjun Chen
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Kuifeng Tian
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Zuhui Pu
- Imaging Department, Shenzhen Institute of Translational Medicine, Health Science Center, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Yong Ni
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Lisha Mou
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
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24
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Lee SJ, Kim HA, Kim SJ, Lee HA. Improving Generation of Cardiac Organoids from Human Pluripotent Stem Cells Using the Aurora Kinase Inhibitor ZM447439. Biomedicines 2021; 9:biomedicines9121952. [PMID: 34944767 PMCID: PMC8698385 DOI: 10.3390/biomedicines9121952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 01/21/2023] Open
Abstract
Drug-induced cardiotoxicity reduces the success rates of drug development. Thus, the limitations of current evaluation methods must be addressed. Human cardiac organoids (hCOs) derived from induced pluripotent stem cells (hiPSCs) are useful as an advanced drug-testing model; they demonstrate similar electrophysiological functionality and drug reactivity as the heart. How-ever, similar to other organoid models, they have immature characteristics compared to adult hearts, and exhibit batch-to-batch variation. As the cell cycle is important for the mesodermal differentiation of stem cells, we examined the effect of ZM447439, an aurora kinase inhibitor that regulates the cell cycle, on cardiogenic differentiation. We determined the optimal concentration and timing of ZM447439 for the differentiation of hCOs from hiPSCs and developed a novel protocol for efficiently and reproducibly generating beating hCOs with improved electrophysiological functionality, contractility, and yield. We validated their maturity through electro-physiological- and image-based functional assays and gene profiling with next-generation sequencing, and then applied these cells to multi-electrode array platforms to monitor the cardio-toxicity of drugs related to cardiac arrhythmia; the results confirmed the drug reactivity of hCOs. These findings may enable determination of the regulatory mechanism of cell cycles underlying the generation of iPSC-derived hCOs, providing a valuable drug testing platform.
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Affiliation(s)
- Su-Jin Lee
- Department of Predictive Toxicology, Korea Institute of Toxicology (KIT), Daejeon 34114, Korea; (S.-J.L.); (H.-A.K.)
- Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hyeon-A Kim
- Department of Predictive Toxicology, Korea Institute of Toxicology (KIT), Daejeon 34114, Korea; (S.-J.L.); (H.-A.K.)
| | - Sung-Joon Kim
- Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: (S.-J.K.); (H.-A.L.); Tel.: +82-2-740-8230 (S.-J.K.); +82-42-610-8093 (H.-A.L.)
| | - Hyang-Ae Lee
- Department of Predictive Toxicology, Korea Institute of Toxicology (KIT), Daejeon 34114, Korea; (S.-J.L.); (H.-A.K.)
- Correspondence: (S.-J.K.); (H.-A.L.); Tel.: +82-2-740-8230 (S.-J.K.); +82-42-610-8093 (H.-A.L.)
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25
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Singh S, Utreja D, Kumar V. Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy. Med Chem Res 2021; 31:1-25. [PMID: 34803342 PMCID: PMC8590428 DOI: 10.1007/s00044-021-02819-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 10/29/2021] [Indexed: 12/21/2022]
Abstract
Cancer is the second leading cause of death worldwide responsible for about 10 million deaths per year. To date several approaches have been developed to treat this deadly disease including surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, and synthetic lethality. The targeted therapy refers to targeting only specific proteins or enzymes that are dysregulated in cancer rather than killing all rapidly dividing cells, has gained much attention in the recent past. Kinase inhibition is one of the most successful approaches in targeted therapy. As of 30 March 2021, FDA has approved 65 small molecule protein kinase inhibitors and most of them are for cancer therapy. Interestingly, several kinase inhibitors contain one or more fused heterocycles as part of their structures. Pyrrolo[2,1-f][1,2,4]triazine is one the most interesting fused heterocycle that is an integral part of several kinase inhibitors and nucleoside drugs viz. avapritinib and remdesivir. This review articles focus on the recent advances made in the development of kinase inhibitors containing pyrrolo[2,1-f][1,2,4]triazine scaffold. ![]()
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Affiliation(s)
- Sarbjit Singh
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198 USA
| | - Divya Utreja
- Department of Chemistry, Punjab Agricultural University, Ludhiana, 141004 Punjab India
| | - Vimal Kumar
- Department of Chemistry, Dr B. R. Ambedkar National Institute of Technology (NIT), Jalandhar, 144011 Punjab India
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26
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Abstract
MicroRNAs (miRNAs), a class of small noncoding RNA, posttranscriptionally regulate the expression of genes. Aberrant expression of miRNA is reported in various types of cancer. Since the first report of oncomiR-21 involvement in the glioma, its upregulation was reported in multiple cancers and was allied with high oncogenic property. In addition to the downregulation of tumor suppressor genes, the miR-21 is also associated with cancer resistance to various chemotherapy. The recent research is appraising miR-21 as a promising cancer target and biomarker for early cancer detection. In this review, we briefly explain the biogenesis and regulation of miR-21 in cancer cells. Additionally, the review features the assorted genes/pathways regulated by the miR-21 in various cancer and cancer stem cells.
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27
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Nair JJ, van Staden J. Cytotoxic Agents in the Minor Alkaloid Groups of the Amaryllidaceae. PLANTA MEDICA 2021; 87:916-936. [PMID: 33706400 DOI: 10.1055/a-1380-1888] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Over 600 alkaloids have to date been identified in the plant family Amaryllidaceae. These have been arranged into as many as 15 different groups based on their characteristic structural features. The vast majority of studies on the biological properties of Amaryllidaceae alkaloids have probed their anticancer potential. While most efforts have focused on the major alkaloid groups, the volume and diversity afforded by the minor alkaloid groups have promoted their usefulness as targets for cancer cell line screening purposes. This survey is an in-depth review of such activities described for around 90 representatives from 10 minor alkaloid groups of the Amaryllidaceae. These have been evaluated against over 60 cell lines categorized into 18 different types of cancer. The montanine and cripowellin groups were identified as the most potent, with some in the latter demonstrating low nanomolar level antiproliferative activities. Despite their challenging molecular architectures, the minor alkaloid groups have allowed for facile adjustments to be made to their structures, thereby altering the size, geometry, and electronics of the targets available for structure-activity relationship studies. Nevertheless, it was seen with a regular frequency that the parent alkaloids were better cytotoxic agents than the corresponding semisynthetic derivatives. There has also been significant interest in how the minor alkaloid groups manifest their effects in cancer cells. Among the various targets and pathways in which they were seen to mediate, their ability to induce apoptosis in cancer cells is most appealing.
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Affiliation(s)
- Jerald J Nair
- Research Centre for Plant Growth and Development, University of KwaZulu-Natal Pietermaritzburg, Scottsville, South Africa
| | - Johannes van Staden
- Research Centre for Plant Growth and Development, University of KwaZulu-Natal Pietermaritzburg, Scottsville, South Africa
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Ashraf S, Ranaghan KE, Woods CJ, Mulholland AJ, Ul-Haq Z. Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach. Sci Rep 2021; 11:18707. [PMID: 34548506 PMCID: PMC8455585 DOI: 10.1038/s41598-021-97368-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 07/21/2021] [Indexed: 02/04/2023] Open
Abstract
Aurora kinase B plays an important role in the cell cycle to orchestrate the mitotic process. The amplification and overexpression of this kinase have been implicated in several human malignancies. Therefore, Aurora kinase B is a potential drug target for anticancer therapies. Here, we combine atom-based 3D-QSAR analysis and pharmacophore model generation to identify the principal structural features of acylureidoindolin derivatives that could potentially be responsible for the inhibition of Aurora kinase B. The selected CoMFA and CoMSIA model showed significant results with cross-validation values (q2) of 0.68, 0.641 and linear regression values (r2) of 0.971, 0.933 respectively. These values support the statistical reliability of our model. A pharmacophore model was also generated, incorporating features of reported crystal complex structures of Aurora kinase B. The pharmacophore model was used to screen commercial databases to retrieve potential lead candidates. The resulting hits were analyzed at each stage for diversity based on the pharmacophore model, followed by molecular docking and filtering based on their interaction with active site residues and 3D-QSAR predictions. Subsequently, MD simulations and binding free energy calculations were performed to test the predictions and to characterize interactions at the molecular level. The results suggested that the identified compounds retained the interactions with binding residues. Binding energy decomposition identified residues Glu155, Trp156 and Ala157 of site B and Leu83 and Leu207 of site C as major contributors to binding affinity, complementary to 3D-QSAR results. To best of our knowledge, this is the first comparison of WaterSwap field and 3D-QSAR maps. Overall, this integrated strategy provides a basis for the development of new and potential AK-B inhibitors and is applicable to other protein targets.
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Affiliation(s)
- Sajda Ashraf
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
- Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK
| | - Kara E Ranaghan
- Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK
| | - Christopher J Woods
- Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK
| | - Adrian J Mulholland
- Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK.
| | - Zaheer Ul-Haq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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29
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Ji CM, Zhang X, Fang W, Meng L, Wei X, Lu C. RNA-binding protein RNPC1 acts as an oncogene in gastric cancer by stabilizing aurora kinase B mRNA. Exp Cell Res 2021; 406:112741. [PMID: 34302858 DOI: 10.1016/j.yexcr.2021.112741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/09/2021] [Accepted: 07/19/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND RNPC1 is reported to act as a tumor suppressor by binding and regulating the expression of target genes in various cancers. However, the role of RNPC1 in gastric cancer and the underlying mechanisms are still unclear. METHODS Gastric cancer cells were stably transfected with lentivirus. Proliferation, migration, invasion, cell cycle in vitro and tumorigenesis in vivo were used to assess the role of RNPC1. Quantitative real-time PCR, western blotting and immunohistochemistry were used to detect the relationship between RNPC1 and aurora kinase B (AURKB). RNA immunoprecipitation (RIP), RNA electrophoretic mobility shift assays (REMSAs), and dual-luciferase reporter assays were used to identify the direct binding sites of RNPC1 with AURKB mRNA. A CCK-8 assay was conducted to confirm the function of AURKB in RNPC1-induced growth promotion. RESULTS High RNPC1 expression was found in gastric cancer tissues and cell lines and was associated with high TNM stage. RNPC1 overexpression significantly promoted the proliferation, migration, and invasion of gastric cancer cells. Knockdown of RNPC1 could impede gastric cancer tumorigenesis in nude mice. AURKB expression was positively related to RNPC1. RNPC1 directly binds to the 3'-untranslated region (3'-UTR) of AURKB and enhances AURKB mRNA stability. AURKB reversed the proliferation induced by RNPC1 in gastric cancer cells. RNPC1 resulted in mitotic defects, aneuploidy and chromosomal instability in gastric cancer cells, similar to AURKB. CONCLUSION RNPC1 acts as an oncogene in gastric cancer by influencing cell mitosis by increasing AURKB mRNA stability, which may provide a potential biomarker and a therapeutic target for gastric cancer.
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Affiliation(s)
- Chun-Mei Ji
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China; Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Xu Zhang
- Jiangsu Breast Disease Center, The First Affliated Hospital with Nanjing Medical University, Nanjing City, Jiangsu Province, 210000, China
| | - Wentong Fang
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Ling Meng
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Xiaolong Wei
- Department of Pathology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, China.
| | - Chen Lu
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
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30
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Pajpach F, Shearwin-Whyatt L, Grützner F. Evolution, Expression and Meiotic Behavior of Genes Involved in Chromosome Segregation of Monotremes. Genes (Basel) 2021; 12:1320. [PMID: 34573302 PMCID: PMC8470780 DOI: 10.3390/genes12091320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 11/16/2022] Open
Abstract
Chromosome segregation at mitosis and meiosis is a highly dynamic and tightly regulated process that involves a large number of components. Due to the fundamental nature of chromosome segregation, many genes involved in this process are evolutionarily highly conserved, but duplications and functional diversification has occurred in various lineages. In order to better understand the evolution of genes involved in chromosome segregation in mammals, we analyzed some of the key components in the basal mammalian lineage of egg-laying mammals. The chromosome passenger complex is a multiprotein complex central to chromosome segregation during both mitosis and meiosis. It consists of survivin, borealin, inner centromere protein, and Aurora kinase B or C. We confirm the absence of Aurora kinase C in marsupials and show its absence in both platypus and echidna, which supports the current model of the evolution of Aurora kinases. High expression of AURKBC, an ancestor of AURKB and AURKC present in monotremes, suggests that this gene is performing all necessary meiotic functions in monotremes. Other genes of the chromosome passenger complex complex are present and conserved in monotremes, suggesting that their function has been preserved in mammals. Cohesins are another family of genes that are of vital importance for chromosome cohesion and segregation at mitosis and meiosis. Previous work has demonstrated an accumulation and differential loading of structural maintenance of chromosomes 3 (SMC3) on the platypus sex chromosome complex at meiotic prophase I. We investigated if a similar accumulation occurs in the echidna during meiosis I. In contrast to platypus, SMC3 was only found on the synaptonemal complex in echidna. This indicates that the specific distribution of SMC3 on the sex chromosome complex may have evolved specifically in platypus.
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Affiliation(s)
| | | | - Frank Grützner
- School of Biological Sciences, The University of Adelaide, Adelaide, SA 5005, Australia; (F.P.); (L.S.-W.)
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31
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Novais P, Silva PMA, Amorim I, Bousbaa H. Second-Generation Antimitotics in Cancer Clinical Trials. Pharmaceutics 2021; 13:1011. [PMID: 34371703 PMCID: PMC8309102 DOI: 10.3390/pharmaceutics13071011] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/24/2021] [Accepted: 06/29/2021] [Indexed: 12/17/2022] Open
Abstract
Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA's effectiveness. With the desire to overcome some of the MTA's limitations, mitotic and SAC components have attracted great interest as promising microtubule-independent targets, leading to the so-called second-generation antimitotics (SGAs). The identification of inhibitors against most of these targets, and the promising outcomes achieved in preclinical assays, has sparked the interest of academia and industry. Many of these inhibitors have entered clinical trials; however, they exhibited limited efficacy as monotherapy, and failed to go beyond phase II trials. Combination therapies are emerging as promising strategies to give a second chance to these SGAs. Here, an updated view of the SGAs that reached clinical trials is here provided, together with future research directions, focusing on inhibitors that target the SAC components.
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Affiliation(s)
- Pedro Novais
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal; (P.N.); (P.M.A.S.)
- Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
- ICBAS, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - Patrícia M. A. Silva
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal; (P.N.); (P.M.A.S.)
| | - Isabel Amorim
- GreenUPorto (Sustainable Agrifood Production) Research Center, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal;
| | - Hassan Bousbaa
- CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal; (P.N.); (P.M.A.S.)
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32
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Hulverson MA, Choi R, Vidadala RSR, Whitman GR, Vidadala VN, Ojo KK, Barrett LK, Lynch JJ, Marsh K, Kempf DJ, Maly DJ, Van Voorhis WC. Pyrrolopyrimidine Bumped Kinase Inhibitors for the Treatment of Cryptosporidiosis. ACS Infect Dis 2021; 7:1200-1207. [PMID: 33565854 PMCID: PMC8559537 DOI: 10.1021/acsinfecdis.0c00803] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Bumped kinase inhibitors (BKIs) that target Cryptosporidium parvum calcium-dependent protein kinase 1 have been well established as potential drug candidates against cryptosporidiosis. Recently, BKI-1649, with a 7H-pyrrolo[2,3-d]pyrimidin-4-amine, or "pyrrolopyrimidine", central scaffold, has shown improved efficacy in mouse models of Cryptosporidium at substantially reduced doses compared to previously explored analogs of the pyrazolopyrimidine scaffold. Here, two pyrrolopyrimidines with varied substituent groups, BKI-1812 and BKI-1814, were explored in several in vitro and in vivo models and show improvements in potency over the previously utilized pyrazolopyrimidine bumped kinase inhibitors while maintaining equivalent results in other key properties, such as toxicity and efficacy, with their pyrazolopyrimidine isosteric counterparts.
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Affiliation(s)
- Matthew A. Hulverson
- Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA
| | - Ryan Choi
- Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA
| | | | - Grant R. Whitman
- Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA
| | | | - Kayode K. Ojo
- Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA
| | - Lynn K. Barrett
- Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA
| | - James J. Lynch
- Research and Development, AbbVie Inc., North Chicago, IL, 60064, USA
| | - Kennan Marsh
- Research and Development, AbbVie Inc., North Chicago, IL, 60064, USA
| | - Dale J. Kempf
- Research and Development, AbbVie Inc., North Chicago, IL, 60064, USA
| | - Dustin J. Maly
- Department of Chemistry, University of Washington, Seattle, 98195, USA
- Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
| | - Wesley C. Van Voorhis
- Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Disease (CERID), University of Washington, Seattle, WA, 98109, USA
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33
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Design, synthesis and molecular docking study of new purine derivatives as Aurora kinase inhibitors. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2020.129843] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer. Molecules 2021; 26:molecules26071981. [PMID: 33915740 PMCID: PMC8037052 DOI: 10.3390/molecules26071981] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 12/23/2022] Open
Abstract
Aurora kinase B (AURKB) is a mitotic serine/threonine protein kinase that belongs to the aurora kinase family along with aurora kinase A (AURKA) and aurora kinase C (AURKC). AURKB is a member of the chromosomal passenger protein complex and plays a role in cell cycle progression. Deregulation of AURKB is observed in several tumors and its overexpression is frequently linked to tumor cell invasion, metastasis and drug resistance. AURKB has emerged as an attractive drug target leading to the development of small molecule inhibitors. This review summarizes recent findings pertaining to the role of AURKB in tumor development, therapy related drug resistance, and its inhibition as a potential therapeutic strategy for cancer. We discuss AURKB inhibitors that are in preclinical and clinical development and combination studies of AURKB inhibition with other therapeutic strategies.
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35
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Kim HJ, Kim J. OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase. Int J Mol Sci 2021; 22:ijms22041936. [PMID: 33669244 PMCID: PMC7919836 DOI: 10.3390/ijms22041936] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/25/2022] Open
Abstract
Aurora kinases are serine/threonine kinases required for cell proliferation and are overexpressed in many human cancers. Targeting Aurora kinases has been a therapeutic strategy in cancer treatment. Here, we attempted to identify a deubiquitinase (DUB) that regulates Aurora kinase A (Aurora-A) protein stability and/or kinase activity as a potential cancer therapeutic target. Through pull-down assays with the human DUB library, we identified OTUD6A as an Aurora-A-specific DUB. OTUD6A interacts with Aurora-A through OTU and kinase domains, respectively, and deubiquitinates Aurora-A. Notably, OTUD6A promotes the protein half-life of Aurora-A and activates Aurora-A by increasing phosphorylation at threonine 288 of Aurora-A. From qPCR screening, we identified and validated that the cancer gene CKS2 encoding Cyclin-dependent kinases regulatory subunit 2 is the most upregulated cell cycle regulator when OTUD6A is overexpressed. The results suggest that OTUD6A may serve as a therapeutic target in human cancers.
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36
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Boussios S, Mikropoulos C, Samartzis E, Karihtala P, Moschetta M, Sheriff M, Karathanasi A, Sadauskaite A, Rassy E, Pavlidis N. Wise Management of Ovarian Cancer: On the Cutting Edge. J Pers Med 2020; 10:E41. [PMID: 32455595 PMCID: PMC7354604 DOI: 10.3390/jpm10020041] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/13/2020] [Accepted: 05/19/2020] [Indexed: 12/11/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20-40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.
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Affiliation(s)
- Stergios Boussios
- Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK; (M.S.); (A.K.); (A.S.)
- AELIA Organization, 9th Km Thessaloniki—Thermi, 57001 Thessaloniki, Greece
| | - Christos Mikropoulos
- St Luke’s Cancer Center, Royal Surrey County Hospital, Egerton Rd, Guildford GU2 7XX, UK;
| | - Eleftherios Samartzis
- Division of Gynecology, University Hospital Zurich, Frauenklinikstrasse 10, CH-8091 Zürich, Switzerland;
| | - Peeter Karihtala
- Department of Oncology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, P.O. Box 100, FI-00029 Helsinki, Finland;
| | - Michele Moschetta
- Cambridge University Hospitals NHS Foundation Trust, Hills Rd, Cambridge CB2 0QQ, UK;
| | - Matin Sheriff
- Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK; (M.S.); (A.K.); (A.S.)
| | - Afroditi Karathanasi
- Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK; (M.S.); (A.K.); (A.S.)
| | - Agne Sadauskaite
- Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK; (M.S.); (A.K.); (A.S.)
| | - Elie Rassy
- Department of Cancer Medicine, Gustave Roussy Institut, 94805 Villejuif, France;
- Department of Hematology-Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut 166830, Lebanon
| | - Nicholas Pavlidis
- Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece;
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Fulcher LJ, Sapkota GP. Mitotic kinase anchoring proteins: the navigators of cell division. Cell Cycle 2020; 19:505-524. [PMID: 32048898 PMCID: PMC7100989 DOI: 10.1080/15384101.2020.1728014] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/14/2020] [Accepted: 02/06/2020] [Indexed: 02/07/2023] Open
Abstract
The coordinated activities of many protein kinases, acting on multiple protein substrates, ensures the error-free progression through mitosis of eukaryotic cells. Enormous research effort has thus been devoted to studying the roles and regulation of these mitotic kinases, and to the identification of their physiological substrates. Central for the timely deployment of specific protein kinases to their appropriate substrates during the cell division cycle are the many anchoring proteins, which serve critical regulatory roles. Through direct association, anchoring proteins are capable of modulating the catalytic activity and/or sub-cellular distribution of the mitotic kinases they associate with. The key roles of some anchoring proteins in cell division are well-established, whilst others are still being unearthed. Here, we review the current knowledge on anchoring proteins for some mitotic kinases, and highlight how targeting anchoring proteins for inhibition, instead of the mitotic kinases themselves, could be advantageous for disrupting the cell division cycle.
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Affiliation(s)
- Luke J Fulcher
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, Scotland, UK
| | - Gopal P Sapkota
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, Scotland, UK
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38
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Cervello M, Emma MR, Augello G, Cusimano A, Giannitrapani L, Soresi M, Akula SM, Abrams SL, Steelman LS, Gulino A, Belmonte B, Montalto G, McCubrey JA. New landscapes and horizons in hepatocellular carcinoma therapy. Aging (Albany NY) 2020; 12:3053-3094. [PMID: 32018226 PMCID: PMC7041742 DOI: 10.18632/aging.102777] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 01/12/2020] [Indexed: 04/12/2023]
Abstract
Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient.
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Affiliation(s)
- Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Maria R. Emma
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Lydia Giannitrapani
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maurizio Soresi
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Shaw M. Akula
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Stephen L. Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Linda S. Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Alessandro Gulino
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Beatrice Belmonte
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
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Liu K, Kang M, Liao X, Wang R. Genome-wide investigation of the clinical significance and prospective molecular mechanism of minichromosome maintenance protein family genes in patients with Lung Adenocarcinoma. PLoS One 2019; 14:e0219467. [PMID: 31323040 PMCID: PMC6641114 DOI: 10.1371/journal.pone.0219467] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Our current study is to identify clinical significance of minichromosome maintenance (MCM) gene expression in Lung Adenocarcinoma (LUAD) using genome-wide RNA sequencing (RNA-seq) dataset and bioinformatics analysis tools. The biological function and potential process for function of the MCM1-10 were identified by multiple bioinformatics analysis tools. Clinical significance and molecular mechanism of the MCM1-10 were investigated by the RNA-seq dataset of LUAD from The Cancer Genome Atlas. Functional assessment substantiated involvement of MCM1-10 in cell cycle progression and DNA replication, and co-expressed with each other. We also observed that the MCM1-10 were dysregulation in LUAD tumor tissues, and may be have diagnostic implications in LUAD. Prognosis analysis in TCGA and KM plotter cohorts suggest that high abundance of MCM5, MCM8 and MCM4 notably correlated to poor LUAD overall survival. Mechanistic exploration of MCM4, MCM5, and MCM8 by gene set enrichment analysis suggests that these genes may influence the LUAD prognosis by regulating the cell cycle, DNA replication and other multiple biological processes and pathways. In comclusion, our study suggests that MCM1-10 can serve as diagnostic biomarkers for LUAD patients. Of them, MCM4, MCM5, and MCM8 may act as potential prognostic indicators for LUAD.
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Affiliation(s)
- Kang Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Min Kang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Rensheng Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- * E-mail:
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Magd-El-Din AA, Mousa HA, Labib AA, Hassan AS, Abd El-All AS, Ali MM, El-Rashedy AA, El-Desoky AH. Benzimidazole - Schiff bases and their complexes: synthesis, anticancer activity and molecular modeling as Aurora kinase inhibitor. ACTA ACUST UNITED AC 2019; 73:465-478. [PMID: 30205654 DOI: 10.1515/znc-2018-0010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 08/04/2018] [Indexed: 11/15/2022]
Abstract
A new series of Schiff bases containing benzіmidazole moiety 11-17 were synthesized by the reaction of 4-(1H-benzо[d]іmіdazоl-2-yl)anіline (1) with different aromatic aldehydes (4-10) via conventional heating and microwave irradiation methods. The structures of the novel Schiff bases were characterized by using different spectral data. Also, metal complexes 18-21 of compound 13 were synthesized, and their structure was confirmed by spectral measurements (IR, NMR, UV), molar conductivity, magnetic susceptibility and thermo-gravimetric analysis. The novel synthesized ligand 13 and its complexes 18-21 were tested for their in vitro antitumor activities towards breast, liver and lung cancer cell lines. Also, the acute toxicity of the prepared compounds 13 and 18-21 was determined in vivo. The results showed that the newly synthesized compounds 13 and 18-21 exhibited a significant activity against cancer, especially for complex 21, compared to standard drug doxorubicin. The molecular docking of complexes 20 and 21 has been also studied as Aurora kinase inhibitors.
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Affiliation(s)
- Asmaa A Magd-El-Din
- Department of Natural and Microbial Product, National Research Centre, Dokki 12622, Giza, Egypt, Phone: +20233370743
| | - Hanan A Mousa
- Department of Inorganic Chemistry, National Research Centre, Dokki 12622, Giza, Egypt
| | - Ammar A Labib
- Department of Inorganic Chemistry, National Research Centre, Dokki 12622, Giza, Egypt
| | - Ashraf S Hassan
- Department of Organometallic and Organometalloid Chemistry, National Research Centre, Dokki 12622, Giza, Egypt
| | - Amira S Abd El-All
- Department of Natural and Microbial Product, National Research Centre, Dokki 12622, Giza, Egypt
| | - Mamdouh M Ali
- Department of Biochemistry, National Research Centre, Dokki 12622, Giza, Egypt
| | - Ahmed A El-Rashedy
- Department of Natural and Microbial Product, National Research Centre, Dokki 12622, Giza, Egypt
| | - Ahmed H El-Desoky
- Department of Pharmacognosy, National Research Centre, Dokki 12622, Giza, Egypt
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Bathula R, Lanka G, Muddagoni N, Dasari M, Nakkala S, Bhargavi M, Somadi G, Sivan SK, Rajender Potlapally S. Identification of potential Aurora kinase-C protein inhibitors: an amalgamation of energy minimization, virtual screening, prime MMGBSA and AutoDock. J Biomol Struct Dyn 2019; 38:2314-2325. [DOI: 10.1080/07391102.2019.1630318] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Revanth Bathula
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Goverdhan Lanka
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Narasimha Muddagoni
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Mahendar Dasari
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Sravanthi Nakkala
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Manan Bhargavi
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Gururaj Somadi
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Sree Kanth Sivan
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
| | - Sarita Rajender Potlapally
- Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Hyderabad, India
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Falchook G, Coleman RL, Roszak A, Behbakht K, Matulonis U, Ray-Coquard I, Sawrycki P, Duska LR, Tew W, Ghamande S, Lesoin A, Schwartz PE, Buscema J, Fabbro M, Lortholary A, Goff B, Kurzrock R, Martin LP, Gray HJ, Fu S, Sheldon-Waniga E, Lin HM, Venkatakrishnan K, Zhou X, Leonard EJ, Schilder RJ. Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial. JAMA Oncol 2019; 5:e183773. [PMID: 30347019 DOI: 10.1001/jamaoncol.2018.3773] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Importance There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration ClinicalTrials.gov identifier: NCT01091428.
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Affiliation(s)
- Gerald Falchook
- Sarah Cannon Research Institute at HealthONE, Denver, Colorado
| | | | - Andrzej Roszak
- Greater Poland Cancer Centre/University of Medical Sciences, Poznan, Poland
| | - Kian Behbakht
- Department of Gynecologic Oncology, University of Colorado School of Medicine, Aurora
| | - Ursula Matulonis
- Gynecologic Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Piotr Sawrycki
- Department of Oncology and Chemotherapy, L. Rydygiera District Hospital, Torun, Poland
| | - Linda R Duska
- University of Virginia Health System, Charlottesville
| | - William Tew
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sharad Ghamande
- Georgia Cancer Center at Augusta University, Augusta, Georgia
| | | | | | | | | | | | | | | | | | | | - Siqing Fu
- University of Texas, MD Anderson Cancer Center, Houston
| | - Emily Sheldon-Waniga
- Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachusetts
| | - Huamao Mark Lin
- Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachusetts
| | - Karthik Venkatakrishnan
- Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachusetts
| | - Xiaofei Zhou
- Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachusetts
| | - E Jane Leonard
- Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, Massachusetts
| | - Russell J Schilder
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
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Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN, Rogister B. The functional diversity of Aurora kinases: a comprehensive review. Cell Div 2018; 13:7. [PMID: 30250494 PMCID: PMC6146527 DOI: 10.1186/s13008-018-0040-6] [Citation(s) in RCA: 263] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 09/05/2018] [Indexed: 02/07/2023] Open
Abstract
Aurora kinases are serine/threonine kinases essential for the onset and progression of mitosis. Aurora members share a similar protein structure and kinase activity, but exhibit distinct cellular and subcellular localization. AurA favors the G2/M transition by promoting centrosome maturation and mitotic spindle assembly. AurB and AurC are chromosome-passenger complex proteins, crucial for chromosome binding to kinetochores and segregation of chromosomes. Cellular distribution of AurB is ubiquitous, while AurC expression is mainly restricted to meiotically-active germ cells. In human tumors, all Aurora kinase members play oncogenic roles related to their mitotic activity and promote cancer cell survival and proliferation. Furthermore, AurA plays tumor-promoting roles unrelated to mitosis, including tumor stemness, epithelial-to-mesenchymal transition and invasion. In this review, we aim to understand the functional interplay of Aurora kinases in various types of human cells, including tumor cells. The understanding of the functional diversity of Aurora kinases could help to evaluate their relevance as potential therapeutic targets in cancer.
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Affiliation(s)
- Estelle Willems
- 1Laboratory of Nervous System Diseases and Therapy, GIGA-Neuroscience, University of Liège, Avenue Hippocrate, 15, 4000 Liège, Belgium
| | - Matthias Dedobbeleer
- 1Laboratory of Nervous System Diseases and Therapy, GIGA-Neuroscience, University of Liège, Avenue Hippocrate, 15, 4000 Liège, Belgium
| | - Marina Digregorio
- 1Laboratory of Nervous System Diseases and Therapy, GIGA-Neuroscience, University of Liège, Avenue Hippocrate, 15, 4000 Liège, Belgium
| | - Arnaud Lombard
- 1Laboratory of Nervous System Diseases and Therapy, GIGA-Neuroscience, University of Liège, Avenue Hippocrate, 15, 4000 Liège, Belgium.,2Department of Neurosurgery, CHU of Liège, Liège, Belgium
| | - Paul Noel Lumapat
- 1Laboratory of Nervous System Diseases and Therapy, GIGA-Neuroscience, University of Liège, Avenue Hippocrate, 15, 4000 Liège, Belgium.,3Department of Neurology, CHU of Liège, Liège, Belgium
| | - Bernard Rogister
- 1Laboratory of Nervous System Diseases and Therapy, GIGA-Neuroscience, University of Liège, Avenue Hippocrate, 15, 4000 Liège, Belgium.,3Department of Neurology, CHU of Liège, Liège, Belgium
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A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma. MOLECULAR THERAPY-NUCLEIC ACIDS 2018; 13:176-188. [PMID: 30292139 PMCID: PMC6172479 DOI: 10.1016/j.omtn.2018.08.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 08/07/2018] [Accepted: 08/19/2018] [Indexed: 02/08/2023]
Abstract
Currently, sorafenib-based therapy is the standard treatment for advanced hepatocellular carcinoma (HCC), and there is a strong rationale for investigating its use in combination with other agents to achieve better therapeutic effects. Aurora-A, a member of a family of mitotic serine/threonine kinases, is frequently overexpressed in human cancers and therefore represents a target for therapy. Here, we investigated a novel Aurora-A inhibitor, MLN8237, together with sorafenib in HCC cells in vitro and in vivo, and elucidated the possible molecular mechanism. Here, it was found that MLN8237 was strongly synergistic with sorafenib in inhibition of HCC progression by altering cell growth, cell-cycle regulation, apoptosis, migration, invasion, and angiogenesis. Mechanism dissection suggests that the combination of MLN8237 and sorafenib led to significant inhibition of the activation of phospho-Akt (p-Akt) and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) and their downstream genes including CDK4, cyclinD1, and VEGFA. The activators of p-Akt and p-p38 MAPK signaling partially reversed the synergistic inhibitory effects of sorafenib and MLN8237 on HCC progression. Subsequent in vivo studies further confirmed the synergistic effects of sorafenib and MLN8237. Collectively, the newly developed sorafenib-MLN8237 combination may be a novel therapy to better inhibit HCC progression.
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Long L, Wang YH, Zhuo JX, Tu ZC, Wu R, Yan M, Liu Q, Lu G. Structure-based drug design: Synthesis and biological evaluation of quinazolin-4-amine derivatives as selective Aurora A kinase inhibitors. Eur J Med Chem 2018; 157:1361-1375. [DOI: 10.1016/j.ejmech.2018.08.053] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 08/17/2018] [Accepted: 08/18/2018] [Indexed: 11/26/2022]
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Kelly KR, Friedberg JW, Park SI, McDonagh K, Hayslip J, Persky D, Ruan J, Puvvada S, Rosen P, Iyer SP, Stefanovic A, Bernstein SH, Weitman S, Karnad A, Monohan G, VanderWalde A, Mena R, Schmelz M, Spier C, Groshen S, Venkatakrishnan K, Zhou X, Sheldon-Waniga E, Leonard EJ, Mahadevan D. Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma. Clin Cancer Res 2018; 24:6150-6159. [PMID: 30082475 DOI: 10.1158/1078-0432.ccr-18-0286] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/08/2018] [Accepted: 07/31/2018] [Indexed: 12/20/2022]
Abstract
PURPOSE The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. PATIENTS AND METHODS Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. RESULTS Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.
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Affiliation(s)
- Kevin R Kelly
- USC Norris Comprehensive Cancer Center, Los Angeles, California (previously University of Texas Health Science Center at San Antonio, San Antonio, Texas).
| | | | - Steven I Park
- Levine Cancer Institute and Carolinas Healthcare System, Charlotte, North Carolina
| | - Kevin McDonagh
- Vanderbilt University, Nashville, Tennessee (previously University of Kentucky Markey Cancer Center, Lexington, Kentucky)
| | - John Hayslip
- University of Kentucky Markey Cancer Center, Lexington, Kentucky
| | | | - Jia Ruan
- Weill Cornell Medical College, New York, New York
| | | | - Peter Rosen
- Providence St Joseph Medical Center, Disney Family Cancer Center, Burbank, California
| | | | - Alexandra Stefanovic
- University of Miami Miller School of Medicine, Sylvester Cancer Center, Miami, Florida
| | | | - Steven Weitman
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Anand Karnad
- University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Gregory Monohan
- University of Kentucky Markey Cancer Center, Lexington, Kentucky
| | - Ari VanderWalde
- University of Tennessee Health Science Center and West Clinic, Memphis, Tennessee
| | - Raul Mena
- Providence St Joseph Medical Center, Disney Family Cancer Center, Burbank, California
| | - Monika Schmelz
- Department of Pathology, College of Medicine, University of Arizona, Tucson, Arizona
| | - Catherine Spier
- Department of Pathology, College of Medicine, University of Arizona, Tucson, Arizona
| | - Susan Groshen
- USC Norris Comprehensive Cancer Center, Los Angeles, California (previously University of Texas Health Science Center at San Antonio, San Antonio, Texas)
| | - Karthik Venkatakrishnan
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Xiaofei Zhou
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Emily Sheldon-Waniga
- Bluebird Bio, Cambridge, Massachusetts (previously Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited)
| | - E Jane Leonard
- Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
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DeLuca JG. Aurora A Kinase Function at Kinetochores. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY 2018; 82:91-99. [PMID: 29700233 DOI: 10.1101/sqb.2017.82.034991] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
One of the most important regulatory aspects of chromosome segregation is the ability of kinetochores to precisely control their attachment strength to spindle microtubules. Central to this regulation is Aurora B, a mitotic kinase that phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the kinetochore protein Ndc80/Hec1, which is a component of the NDC80 complex, the primary force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the "master regulator" of kinetochore-microtubule attachment, it is becoming clear that this kinase is not solely responsible for phosphorylating Hec1 and other kinetochore substrates to facilitate microtubule turnover. In particular, there is growing evidence that Aurora A kinase, whose activities at spindle poles have been extensively described, has additional roles at kinetochores in regulating the kinetochore-microtubule interface.
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Affiliation(s)
- Jennifer G DeLuca
- Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870
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Umstead M, Xiong J, Qi Q, Du Y, Fu H. Aurora kinase A interacts with H-Ras and potentiates Ras-MAPK signaling. Oncotarget 2018; 8:28359-28372. [PMID: 28177880 PMCID: PMC5438655 DOI: 10.18632/oncotarget.15049] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 01/07/2017] [Indexed: 11/25/2022] Open
Abstract
In cancer, upregulated Ras promotes cellular transformation and proliferation in part through activation of oncogenic Ras-MAPK signaling. While directly inhibiting Ras has proven challenging, new insights into Ras regulation through protein-protein interactions may offer unique opportunities for therapeutic intervention. Here we report the identification and validation of Aurora kinase A (Aurora A) as a novel Ras binding protein. We demonstrate that the kinase domain of Aurora A mediates the interaction with the N-terminal domain of H-Ras. Further more, the interaction of Aurora A and H-Ras exists in a protein complex with Raf-1. We show that binding of H-Ras to Raf-1 and subsequent MAPK signaling is enhanced by Aurora A, and requires active H-Ras. Thus, the functional linkage between Aurora A and the H-Ras/Raf-1 protein complex may provide a mechanism for Aurora A's oncogenic activity through direct activation of the Ras/MAPK pathway.
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Affiliation(s)
- MaKendra Umstead
- Graduate Program in Cancer Biology, Emory University, Atlanta, GA, USA.,Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Jinglin Xiong
- Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA.,Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Qi Qi
- Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Yuhong Du
- Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Haian Fu
- Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA.,Winship Cancer Institute, Atlanta, GA, USA
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Recombinant human bone morphogenetic protein-2 inhibits gastric cancer cell proliferation by inactivating Wnt signaling pathway via c-Myc with aurora kinases. Oncotarget 2018; 7:73473-73485. [PMID: 27636990 PMCID: PMC5341992 DOI: 10.18632/oncotarget.11969] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 09/02/2016] [Indexed: 01/12/2023] Open
Abstract
The detailed molecular mechanisms and safety issues of recombinant human bone morphogenetic protein-2 (rhBMP-2) usage in bone graft substitution remain poorly understood. To investigate the molecular mechanisms underlying the function of rhBMP-2 in gastric cancer cells, we used microarrays to determine the gene expression patterns related to the effects of rhBMP-2. Based on a gene ontology analysis, several genes were upregulated during the regulation of the cell cycle and BMP signaling pathway. MYC was found to be significantly decreased along with its downstream target genes, the aurora kinases (AURKs), by rhBMP-2 in the network analysis. We further confirmed this finding with western blot data that rhBMP-2 inhibited c-Myc, AURKs, and β-catenin in SNU484 and SNU638 cells. An AURK inhibitor significantly decreased c-Myc expression in gastric cancer cells. Combination treatment with rhBMP-2 and AURK inhibitor resulted in significantly decreased c-Myc expression compared with gastric cancer cells treated with an rhBMP-2 or AURK inhibitor, respectively. Similar effects for decreased c-Myc expression were observed when we silenced β-catenin in gastric cancer cells. These results indicate that rhBMP-2 attenuated the growth of gastric cancer cells via the inactivation of β-catenin via c-Myc and AURKs. Therefore, our findings suggest that rhBMP-2 could be safely used with patients who undergo gastric or gastroesophageal cancer surgery.
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Liewer S, Huddleston A. Alisertib: a review of pharmacokinetics, efficacy and toxicity in patients with hematologic malignancies and solid tumors. Expert Opin Investig Drugs 2018; 27:105-112. [PMID: 29260599 DOI: 10.1080/13543784.2018.1417382] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib. Promising results are notable in patients with peripheral T cell lymphoma in particular, forming the basis for the first phase 3 randomized trial of alisertib. Although it did show encouraging response rates, it failed to demonstrate superiority over the comparator arm at an interim analysis, halting further enrollment. Expert opinion: Despite disappointing early results, alisertib remains under investigation in a number of cancer types both as monotherapy and in combination with traditional cytotoxic chemotherapy, with encouraging results. Most common toxicities in early trials include myelosuppression alopecia, mucositis and fatigue. The relatively manageable toxicity profile of alisertib along with ease of dosing may allow it to be combined with other oral agents or traditional chemotherapy across a wide variety of malignancy types.
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Affiliation(s)
- Susanne Liewer
- a Department of Pharmacy , Nebraska Medicine , Omaha , NE , USA.,b College of Pharmacy , University of Nebraska Medical Center , Omaha , NE , USA
| | - Ashley Huddleston
- c Department of Pharmacy , Mercy Hospital , Oklahoma City , OK , USA
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