|
1
|
Poodeh AM, Sarab GA, Ravari MP, Najafzadeh M, Safarpour H, Zarban A, Sayadi M, Sajjadi SM. Metformin and chloroquine enhanced the efficacy of cytarabine in acute lymphoblastic leukemia cell lines: a drug repositioning approach. Sci Rep 2025; 15:16510. [PMID: 40360710 PMCID: PMC12075817 DOI: 10.1038/s41598-025-01574-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 05/07/2025] [Indexed: 05/15/2025] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite advances in the treatment of ALL, high disease recurrence and the impact of chemical toxicity on patients' quality of life persist. Drug repositioning has been proven to have antitumor and anti-inflammatory properties in leukemia. This study investigated the effects of metformin and chloroquine on the efficacy of cytarabine in NALM-6 cells. The growth inhibitory effects of metformin (Met) and chloroquine (CQ) on the response of NALM-6 cells to cytarabine (AraC) were determined via the MTT assay. To test the regeneration potential, a colony formation assay was performed. Apoptosis and cell cycle analyses were executed via flow cytometry. Oxidative stress markers and antioxidant activity were measured. Gene expression analysis and protein measurement of apoptotic and signaling pathways were performed. The administration of metformin and chloroquine increased the efficacy of cytarabine in suppressing NALM-6 cells, leading to decreased colony formation, increased apoptosis, and G1 phase cell cycle arrest. These effects are mediated by the upregulation of TP53, CASP3 and CASP8 genes and the reduction in BCL-2, NRAS and KRAS genes. Our data suggest that the combination of AraC with Met and CQ may be an effective approach for the treatment of B-ALL.
Collapse
Affiliation(s)
- Ahmad Moradi Poodeh
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Gholamreza Anani Sarab
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Mahsa Najafzadeh
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Hossein Safarpour
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Asghar Zarban
- Clinical Biochemistry Department, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mahtab Sayadi
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
| | - Seyed Mehdi Sajjadi
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
| |
Collapse
|
|
2
|
Chaudhary N, La Ferlita A, Choudhary BS, Jog E, Kazi M, Yahya S, Dalwai A, Ostwal V, Singh S, Redkar S, Khapare N, Kailaje V, B A, Gera P, Bal M, Verma N, Thorat R, Saklani A, Sehgal L, Dalal SN. Patient-Derived Organoids and Xenografts Uncover Therapeutic Vulnerabilities in Colorectal Signet Ring Cell Carcinomas. Clin Cancer Res 2025; 31:1359-1373. [PMID: 39879477 DOI: 10.1158/1078-0432.ccr-24-2329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/28/2024] [Accepted: 01/24/2025] [Indexed: 01/31/2025]
Abstract
PURPOSE Identifying therapeutic targets for signet ring cell carcinoma (SRCC) of the colon and rectum is a clinical challenge because of the lack of patient-derived organoids (PDO) or patient-derived xenografts (PDX). To address this unmet need, we present a robust method for establishing PDO and PDX models. We demonstrate that these models identify novel therapeutic strategies targeting therapy resistance and peritoneal metastasis. EXPERIMENTAL DESIGN We derived nine PDO and PDX models from patients with colorectal SRCC. Detailed histopathologic characterization confirmed the fidelity of these models to the original tumors. Drug sensitivity assays were conducted in vitro and in vivo to assess the therapeutic efficacy and impact on peritoneal metastasis. An RNA sequencing analysis was performed to identify critical pathways contributing to therapy resistance and metastatic progression. RESULTS We successfully developed and characterized PDO and PDX models from nine patients with SRCC. The SRCC PDO and PDX models exhibited histopathologic features consistent with those of the original tumors, including high mucin content and eccentric nuclei. They demonstrated increased sensitivity to FOLFIRI combined with paclitaxel or vincristine, reducing peritoneal metastasis. RNA sequencing analysis revealed the upregulation of autophagy genes in SRCC. Treatment with chloroquine alone resulted in decreased tumor growth and peritoneal metastasis. CONCLUSIONS Our study establishes PDO and PDX models as robust platforms for studying SRCC and identifying potential therapeutic strategies. Combining FOLFIRI with paclitaxel/vincristine or chloroquine alone inhibits tumor growth and prevents peritoneal metastasis, showing promise for clinical translation. These findings suggest that combining FOLFIRI with intraperitoneal paclitaxel warrants further investigation in phase I clinical trials for patients with SRCC.
Collapse
Affiliation(s)
- Nazia Chaudhary
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Alessandro La Ferlita
- Division of Hematology, College of Medicine, The Ohio State University, Columbus, Ohio
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio
| | - Bhagya Shree Choudhary
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Training School Complex, Mumbai, India
| | - Eeshrita Jog
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Mufaddal Kazi
- Homi Bhabha National Institute, Training School Complex, Mumbai, India
- Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
- Department of Gastrointestinal Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Showket Yahya
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Afiya Dalwai
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Vikas Ostwal
- Department of Gastrointestinal Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
- Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Satishkumar Singh
- Division of Hematology, College of Medicine, The Ohio State University, Columbus, Ohio
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio
| | - Siddhi Redkar
- Electron Microscopy Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Nileema Khapare
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Vaishali Kailaje
- Digital Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Akshaya B
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Poonam Gera
- Department of Biorepository, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Munita Bal
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Nandini Verma
- Homi Bhabha National Institute, Training School Complex, Mumbai, India
- TNBC Precision Medicine Research Group, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Rahul Thorat
- Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
| | - Avanish Saklani
- Homi Bhabha National Institute, Training School Complex, Mumbai, India
- Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
- Department of Gastrointestinal Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India
| | - Lalit Sehgal
- Division of Hematology, College of Medicine, The Ohio State University, Columbus, Ohio
- The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio
| | - Sorab N Dalal
- Cell and Tumor Biology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Training School Complex, Mumbai, India
| |
Collapse
|
|
3
|
Stevens M, Wang Y, Bouley SJ, Mandigo TR, Sharma A, Sengupta S, Housden A, Perrimon N, Walker JA, Housden BE. Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors. Mol Oncol 2025; 19:825-851. [PMID: 39129390 PMCID: PMC11887668 DOI: 10.1002/1878-0261.13704] [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: 12/05/2023] [Revised: 05/29/2024] [Accepted: 07/19/2024] [Indexed: 08/13/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1-deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1-deficient Drosophila cells. When further investigating autophagy-related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1-deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1-deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1-deficient cell viability. In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1-associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.
Collapse
Affiliation(s)
- Megan Stevens
- Living Systems InstituteUniversity of ExeterUK
- Department of Clinical and Biomedical ScienceUniversity of ExeterUK
| | - Yuanli Wang
- Living Systems InstituteUniversity of ExeterUK
- The First People's Hospital of QinzhouChina
| | | | - Torrey R. Mandigo
- Center for Genomic MedicineMassachusetts General HospitalBostonMAUSA
| | - Aditi Sharma
- Center for Genomic MedicineMassachusetts General HospitalBostonMAUSA
| | - Sonali Sengupta
- Living Systems InstituteUniversity of ExeterUK
- Department of Clinical and Biomedical ScienceUniversity of ExeterUK
| | - Amy Housden
- Living Systems InstituteUniversity of ExeterUK
| | - Norbert Perrimon
- Department of Genetics, Blavatnik InstituteHarvard Medical SchoolBostonMAUSA
- Howard Hughes Medical InstituteNew YorkNYUSA
| | - James A. Walker
- Center for Genomic MedicineMassachusetts General HospitalBostonMAUSA
- Cancer ProgramBroad Institute of MIT and HarvardCambridgeMAUSA
- Department of Neurology, Massachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Benjamin E. Housden
- Living Systems InstituteUniversity of ExeterUK
- Department of Clinical and Biomedical ScienceUniversity of ExeterUK
| |
Collapse
|
|
4
|
Benbelkacem M, Moulai N, Chader H, Ouahioune W, Bourouba M. Dichloroacetate and chloroquine in combination with arsenite suppress ROS-induced oral squamous cell carcinoma (OSCC) development and improve BALB/c mice survival. Free Radic Biol Med 2025; 227:593-607. [PMID: 39694118 DOI: 10.1016/j.freeradbiomed.2024.12.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/10/2024] [Accepted: 12/14/2024] [Indexed: 12/20/2024]
Abstract
Oral squamous cell carcinoma (OSCC) is a disabling tumor with poor response to chemotherapy. Here, we sought to explore a new chemotherapeutic approach based on a combined induction of cytotoxic ROS and targeting of autophagy and aerobic glycolysis as central contributors to OSCC carcinogenesis and chemoresistance. To this end, tongue OSCC was generated in BALB/c mice using 4NQO. Treatment of mouse-derived OSSC explants with NaAsO2 resulted in a strong inhibition of MTT activity and Bcl-2 and Ki-67 expression. The addition of chloroquine (CQ) and dichloroacetate (DCA) to arsenite, resulted in additive inhibitory effects on Bcl-2 and Ki-67 expression. Whereas NaAsO2 alone inhibited aerobic glycolysis (LDHA), it also alleviated autophagy (LC3B) and ROS levels (MDA). DCA improved NaAsO2-dependent inhibition of aerobic glycolysis. CQ addition to arsenite, suppressed autophagy without affecting the Warburg effect. NaAsO2 combination with CQ and DCA improved the oxidative status balance by boosting anti-oxidative CAT and SOD and controlling pro-oxidant MDA activity. The administration of the combo to 4NQO-mice resulted in a significant survival advantage over the control group (90 % vs. 35 % survival at week 32, p < 0.02; HR (log-rank) = 0.166, CI 95 % 0.03-0.73). This effect was accompanied by a significant increase in mice's mean body weight (p < 0.009). Contrarily to the control, administration of the combo resulted in the absence of progression towards severe dysplasia and OSCC and an overrepresentation of low/mild dysplasia events (100 %). Interestingly, signs of hepatocellular and renal toxicity following combo administration were limited in comparison to control. Taken together, these results suggest that NaAsO2 combined with CQ and DCA may constitute an interesting alternative to eliminating chemo-resistant OSSC tumors by inhibiting aerobic glycolysis and autophagy and controlling ROS generation. In vivo, the drugs may provide a survival advantage by inhibiting tumor development.
Collapse
Affiliation(s)
- Mounia Benbelkacem
- Laboratory of Cellular and Molecular Biology (LBCM), Team Biotechnology and System Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Bab-Ezzouar, Algiers, Algeria
| | - Nabila Moulai
- Laboratory of Anatomopathology, Frantz Fanon Hospital, Blida: University of Blida, Faculty of Medicine, Algeria
| | - Henni Chader
- Laboratory of Pharmaco-toxicology, National Agency of Pharmaceutical Products, Algiers, Algeria; Faculty of Pharmacy, University of Algiers 1, Algeria
| | - Wahiba Ouahioune
- Laboratory of Anatomopathology, Frantz Fanon Hospital, Blida: University of Blida, Faculty of Medicine, Algeria
| | - Mehdi Bourouba
- Laboratory of Cellular and Molecular Biology (LBCM), Team Biotechnology and System Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Bab-Ezzouar, Algiers, Algeria.
| |
Collapse
|
|
5
|
Satou M, Wang J, Nakano-Tateno T, Teramachi M, Aoki S, Sugimoto H, Chik C, Tateno T. Autophagy inhibition suppresses hormone production and cell growth in pituitary tumor cells: A potential approach to pituitary tumors. Mol Cell Endocrinol 2024; 586:112196. [PMID: 38462123 DOI: 10.1016/j.mce.2024.112196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/12/2024]
Abstract
Pituitary tumors (PTs) represent about 10% of all intracranial tumors, and most are benign. However, some PTs exhibit continued growth despite multimodal therapies. Although temozolomide (TMZ), an alkylating chemotherapeutic agent, is a first-line medical treatment for aggressive PTs, some PTs are resistant to TMZ. Existing literature indicated the involvement of autophagy in cell growth in several types of tumors, including PTs, and autophagy inhibitors have anti-tumor effects. In this study, the expression of several autophagy-inducible genes, including Atg3, Beclin1, Map1lc3A, Map1lc3b, Ulk1, Wipi2, and Tfe3 in two PT cell lines, the mouse corticotroph AtT-20 cells and the rat mammosomatotroph GH4 cells were identified. Down regulation of Tfe3, a master switch of basal autophagy, using RNA interference, suppressed cell proliferation in AtT-20 cells, suggesting basal autophagy contributes to the maintenance of cellular functions in PT cells. Expectedly, treatment with bafilomycin A1, an autophagy inhibitor, suppressed cell proliferation, increased the cleavage of PARP1, and reduced ACTH production in AtT-20 cells. Treatment with two additional autophagy inhibitors, chloroquine (CQ) and monensin, demonstrated similar effects on cell proliferation, apoptosis, and ACTH production in AtT-20 cells. Also, treatment with CQ suppressed cell proliferation and growth hormone production in GH4 cells. Moreover, the combination of CQ and TMZ had an additive effect on the inhibition of cell proliferation in AtT-20 and GH4 cells. The additive effect of anti-cancer drugs such as CQ alone or in combination with TMZ may represent a novel therapeutic approach for PTs, in particular tumors with resistance to TMZ.
Collapse
Affiliation(s)
- Motoyasu Satou
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Jason Wang
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Tae Nakano-Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Mariko Teramachi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Shigeki Aoki
- Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroyuki Sugimoto
- Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Constance Chik
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Toru Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
| |
Collapse
|
|
6
|
Iglesias-Corral D, García-Valles P, Arroyo-Garrapucho N, Bueno-Martínez E, Ruiz-Robles JM, Ovejero-Sánchez M, González-Sarmiento R, Herrero AB. Chloroquine-induced DNA damage synergizes with DNA repair inhibitors causing cancer cell death. Front Oncol 2024; 14:1390518. [PMID: 38803536 PMCID: PMC11128598 DOI: 10.3389/fonc.2024.1390518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024] Open
Abstract
Background Cancer is a global health problem accounting for nearly one in six deaths worldwide. Conventional treatments together with new therapies have increased survival to this devastating disease. However, the persistent challenges of treatment resistance and the limited therapeutic arsenal available for specific cancer types still make research in new therapeutic strategies an urgent need. Methods Chloroquine was tested in combination with different drugs (Panobinostat, KU-57788 and NU-7026) in 8 human-derived cancer cells lines (colorectal: HCT116 and HT29; breast: MDA-MB-231 and HCC1937; glioblastoma: A-172 and LN-18; head and neck: CAL-33 and 32816). Drug´s effect on proliferation was tested by MTT assays and cell death was assessed by Anexin V-PI apoptosis assays. The presence of DNA double-strand breaks was analyzed by phospho-H2AX fluorescent staining. To measure homologous recombination efficiency the HR-GFP reporter was used, which allows flow cytometry-based detection of HR stimulated by I-SceI endonuclease-induced DSBs. Results The combination of chloroquine with any of the drugs employed displayed potent synergistic effects on apoptosis induction, with particularly pronounced efficacy observed in glioblastoma and head and neck cancer cell lines. We found that chloroquine produced DNA double strand breaks that depended on reactive oxygen species formation, whereas Panobinostat inhibited DNA double-strand breaks repair by homologous recombination. Cell death caused by chloroquine/Panobinostat combination were significantly reduced by N-Acetylcysteine, a reactive oxygen species scavenger, underscoring the pivotal role of DSB generation in CQ/LBH-induced lethality. Based on these data, we also explored the combination of CQ with KU-57788 and NU-7026, two inhibitors of the other main DSB repair pathway, nonhomologous end joining (NHEJ), and again synergistic effects on apoptosis induction were observed. Conclusion Our data provide a rationale for the clinical investigation of CQ in combination with DSB inhibitors for the treatment of different solid tumors.
Collapse
Affiliation(s)
- Diego Iglesias-Corral
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Paula García-Valles
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Nuria Arroyo-Garrapucho
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Elena Bueno-Martínez
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Juan Manuel Ruiz-Robles
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - María Ovejero-Sánchez
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Rogelio González-Sarmiento
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Ana Belén Herrero
- Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| |
Collapse
|
|
7
|
Shi S, Luo H, Ji Y, Ouyang H, Wang Z, Wang X, Hu R, Wang L, Wang Y, Xia J, Cheng B, Bao B, Li X, Liao G, Xu B. Repurposing Dihydroartemisinin to Combat Oral Squamous Cell Carcinoma, Associated with Mitochondrial Dysfunction and Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:9595201. [PMID: 37273554 PMCID: PMC10239307 DOI: 10.1155/2023/9595201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/28/2022] [Accepted: 10/06/2022] [Indexed: 08/15/2023]
Abstract
Oral squamous cell carcinoma (OSCC), with aggressive locoregional invasion, has a high rate of early recurrences and poor prognosis. Dihydroartemisinin (DHA), as a derivative of artemisinin, has been found to exert potent antitumor activity. Recent studies reported that DHA suppresses OSCC cell growth and viability through the regulation of reactive oxygen species (ROS) production and mitochondrial calcium uniporter. However, the mechanism underlying the action of DHA on OSCCs remains elusive. In the study, we observed that 159 genes were remarkably misregulated in primary OSCC tumors associated with DHA-inhibited pathways, supporting that OSCCs are susceptible to DHA treatment. Herein, our study showed that DHA exhibited promising effects to suppress OSCC cell growth and survival, and single-cell colony formation. Interestingly, the combination of DHA and cisplatin (CDDP) significantly reduced the toxicity of CDDP treatment alone on human normal oral cells (NOK). Moreover, DHA remarkably impaired mitochondrial structure and function, and triggered DNA damage and ROS generation, and activation of mitophagy. In addition, DHA induced leakage of cytochrome C and apoptosis-inducing factor (AIF) from mitochondria, elevated Bax/cleaved-caspase 3 expression levels and compromised Bcl2 protein expression. In the OSCC tumor-xenograft mice model, DHA remarkably suppressed tumor growth and induced apoptosis of OSCCs in vivo. Intriguingly, a selective mitophagy inhibitor Mdivi-1 could significantly reinforce the anticancer activity of DHA treatment. DHA and Mdivi-1 can synergistically suppress OSCC cell proliferation and survival. These data uncover a previously unappreciated contribution of the mitochondria-associated pathway to the antitumor activity of DHA on OSCCs. Our study shed light on a new aspect of a DHA-based therapeutic strategy to combat OSCC tumors.
Collapse
Affiliation(s)
- Shanwei Shi
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Hospital of Stomatology, Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Huigen Luo
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yuna Ji
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Huiya Ouyang
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zheng Wang
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xinchen Wang
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Renjie Hu
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Lihong Wang
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yun Wang
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Juan Xia
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Bin Cheng
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Baicheng Bao
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xin Li
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- National Engineering Research Center of JUNCAO Technology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Guiqing Liao
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Hospital of Stomatology, Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Baoshan Xu
- Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| |
Collapse
|
|
8
|
Novel 7-Chloro-(4-thioalkylquinoline) Derivatives: Synthesis and Antiproliferative Activity through Inducing Apoptosis and DNA/RNA Damage. Pharmaceuticals (Basel) 2022; 15:ph15101234. [PMID: 36297346 PMCID: PMC9607427 DOI: 10.3390/ph15101234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 11/29/2022] Open
Abstract
A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5-40 and sulfinyl 41-62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63-82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53-/- (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC50) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates.
Collapse
|
|
9
|
Nguyen MT, Choe HC, Kim BH, Ahn SG. A new link between apoptosis induced by the metformin derivative HL156A and autophagy in oral squamous cell carcinoma. Eur J Pharmacol 2022; 920:174859. [DOI: 10.1016/j.ejphar.2022.174859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 02/04/2022] [Accepted: 02/22/2022] [Indexed: 11/03/2022]
|
|
10
|
Abd El-Aziz YS, Leck LYW, Jansson PJ, Sahni S. Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:6152. [PMID: 34944772 PMCID: PMC8699656 DOI: 10.3390/cancers13246152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a cellular catabolic process, which is characterized by degradation of damaged proteins and organelles needed to supply the cell with essential nutrients. At basal levels, autophagy is important to maintain cellular homeostasis and development. It is also a stress responsive process that allows the cells to survive when subjected to stressful conditions such as nutrient deprivation. Autophagy has been implicated in many pathologies including cancer. It is well established that autophagy plays a dual role in different cancer types. There is emerging role of autophagy in oral squamous cell carcinoma (OSCC) development and progression. This review will focus on the role played by autophagy in relation to different aspects of cancer progression and discuss recent studies exploring the role of autophagy in OSCC. It will further discuss potential therapeutic approaches to target autophagy in OSCC.
Collapse
Affiliation(s)
- Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
| |
Collapse
|
|
11
|
Dar-Odeh N, Elsayed S, Babkair H, Abu-Hammad S, Althagafi N, Bahabri R, Eldeen YS, Aljohani W, Abu-Hammad O. What the dental practitioner needs to know about pharmaco-therapeutic modalities of COVID-19 treatment: A review. J Dent Sci 2021; 16:806-816. [PMID: 33230404 PMCID: PMC7674127 DOI: 10.1016/j.jds.2020.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE Several pharmacotherapeutic methods have been used for the treatment of COVID-19 with varying degrees of success. No definitive treatment or vaccine has been officially approved to-date. This review aimed to highlight COVID-19 pharmacotherapeutic agents that are relevant to dental practice in terms of their clinical indications in COVID-19 and dental practice, as well as their adverse effects as they impact the dental patient. MATERIAL AND METHODS Systematic search was performed using the following keywords combinations: Pharmacotherapy AND COVID-19 OR Pharmacotherapy AND SARS-CoV-2 OR Treatment AND COVID-19. Studies were categorized according to the type of pharmacotherapy used. Pharmacotherapeutic agents were extracted and only those relevant to dental practice were included for review. RESULTS For analysis, a total of 79 clinical trials research articles were included that included COVID-19 pharmacotherapeutic agents relevant to dental practice. Those were analgesics (paracetamol; non-steroidal anti-inflammatory agents); antibiotics (azithromycin, doxycycline, metronidazole); antivirals (penciclovir); and immunomodulatory agents (hydroxychloroquine, corticosteroids). While some COVID-19 drugs are less relevant to dental practice, as antivirals and hydroxychloroquine, their association with long-term adverse effects requires adequate knowledge among dental practitioners. CONCLUSION Many of COVID-19 pharmacotherapeutic agents are used to treat oral diseases particularly orofacial pain and inflammatory conditions. Furthermore, some of these drugs may induce adverse effects that complicate dental treatment. Thorough knowledge of COVID-19 therapy and its dental implications is essential for dental practitioners, and is expected to contribute to a better understanding and effective utilization of these therapeutic agents.
Collapse
Affiliation(s)
- Najla Dar-Odeh
- College of Dentistry, Taibah University, Al Madinah, Al Munawara, Saudi Arabia
- School of Dentistry, University of Jordan, Amman, Jordan
| | - Shadia Elsayed
- College of Dentistry, Taibah University, Al Madinah, Al Munawara, Saudi Arabia
- Faculty of Dental Medicine for Girls, Al-Azhar, University, Cairo, Egypt
| | - Hamzah Babkair
- College of Dentistry, Taibah University, Al Madinah, Al Munawara, Saudi Arabia
| | | | - Nebras Althagafi
- College of Dentistry, Taibah University, Al Madinah, Al Munawara, Saudi Arabia
| | - Rayan Bahabri
- College of Dentistry, Taibah University, Al Madinah, Al Munawara, Saudi Arabia
| | | | - Wejdan Aljohani
- College of Dentistry, Taibah University, Al Madinah, Al Munawara, Saudi Arabia
| | - Osama Abu-Hammad
- College of Dentistry, Taibah University, Al Madinah, Al Munawara, Saudi Arabia
- School of Dentistry, University of Jordan, Amman, Jordan
| |
Collapse
|
|
12
|
Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic-Linear-Dendritic Block Copolymers. Int J Mol Sci 2021; 22:ijms22105223. [PMID: 34069278 PMCID: PMC8156097 DOI: 10.3390/ijms22105223] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022] Open
Abstract
Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic® F127 hybrid dendritic–linear–dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2′-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2′-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.
Collapse
|
|
13
|
Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells. Int J Mol Sci 2021; 22:ijms22073682. [PMID: 33916175 PMCID: PMC8037356 DOI: 10.3390/ijms22073682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/19/2022] Open
Abstract
The twofold role of autophagy in cancer is often the therapeutic target. Numerous regulatory pathways are shared between autophagy and other molecular processes needed in tumorigenesis, such as translation or survival signaling. Thus, we have assumed that ILK knockdown should promote autophagy, and used together with chloroquine, an autophagy inhibitor, it could generate a better anticancer effect by dysregulation of common signaling pathways. Expression at the protein level was analyzed using Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Melanoma cell proliferation was assessed with the crystal violet test, and migration was evaluated by scratch wound healing assays. Autophagy was monitored by the accumulation of its marker, LC3-II. Our data show that ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosis. We demonstrated that combinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy with either of these. It generates the synergistic antitumor effects by the decrease of translation of both global and oncogenic proteins synthesis. In our work, we point to the crosstalk between translation and autophagy regulation.
Collapse
|
|
14
|
Munoz-Tello P, Lin H, Khan P, de Vera IMS, Kamenecka TM, Kojetin DJ. Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1. J Med Chem 2020; 63:15639-15654. [PMID: 33289551 PMCID: PMC8006468 DOI: 10.1021/acs.jmedchem.0c00894] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Nurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a drug target for neurological disorders including Alzheimer's and Parkinson's diseases. Previous studies identified small-molecule NR4A nuclear receptor modulators, but it remains unclear if these ligands affect transcription via direct binding to Nurr1. We assessed 12 ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and the ability to bind the Nurr1 ligand-binding domain (LBD). Protein NMR structural footprinting data show that amodiaquine, chloroquine, and cytosporone B bind the Nurr1 LBD; ligands that do not bind include C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), and three high-throughput screening hit derivatives. Importantly, ligands that modulate Nurr1 transcription also show Nurr1-independent effects on transcription in a cell type-specific manner, indicating that care should be taken when interpreting the functional response of these ligands in transcriptional assays. These findings should help focus medicinal chemistry efforts that desire to optimize Nurr1-binding ligands.
Collapse
Affiliation(s)
- Paola Munoz-Tello
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Hua Lin
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Pasha Khan
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Ian Mitchelle S. de Vera
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Theodore M. Kamenecka
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Douglas J. Kojetin
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA
- Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, USA
| |
Collapse
|
|
15
|
Manipulating dynamic tumor vessel permeability to enhance polymeric micelle accumulation. J Control Release 2020; 329:63-75. [PMID: 33278478 DOI: 10.1016/j.jconrel.2020.11.063] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 11/21/2020] [Accepted: 11/30/2020] [Indexed: 01/04/2023]
Abstract
Selectively delivering anticancer drugs to solid tumors while avoiding their accumulation in healthy tissues is a major goal in polymeric micelle research. We have recently discovered that the extravasation and permeation of polymeric micelles occur in a dynamic manner characterized by vascular bursts followed by a brief and vigorous outward flow of fluid (called "nano-eruptions"). Nano-eruptions allow delivery of polymeric micelle-associated drugs, though delivery can be heterogeneous both among tumors and within an individual tumor, leading to suboptimal intratumoral distribution. Manipulation of nano-eruptions is expected to improve the efficiency of drug delivery systems (DDSs). By using compounds that affect the intratumoral environment, i.e. a TGF-β inhibitor and chloroquine, the possibility of manipulating nano-eruptions to improve delivery efficiency was investigated. Both compounds were tested in a mouse xenograft model of GFP-labeled pancreatic tumor cells by tracing nano-eruption events and extravasation of size-modulated polymeric micelles in real-time through intravital confocal laser scanning microscopy. The TGF-β inhibitor increased the number of dynamic vents, extended duration time, and generated dynamic vents with a wide range of sizes. Chloroquine did not affect the frequency of nano-eruptions, but it increased tumor vessel diameter, maximum nano-eruption area, and maximum radial increase. Both the TGF-β inhibitor and chloroquine augmented nano-eruptions to diffuse polymeric micelles through tumor stroma, and these medications had a greater effect on the polymeric micelles with larger size, i.e. 70-nm, than on the smaller polymeric micelles having a 30-nm diameter. The results indicate that TGF-β inhibition and chloroquine refashion the intratumoral distribution of DDSs by different mechanisms.
Collapse
|
|
16
|
COVID-19: Present and Future Challenges for Dental Practice. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17093151. [PMID: 32366034 PMCID: PMC7246705 DOI: 10.3390/ijerph17093151] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 04/26/2020] [Accepted: 04/29/2020] [Indexed: 12/15/2022]
Abstract
COVID-19 was declared a pandemic by the World Health Organization, with a high fatality rate that may reach 8%. The disease is caused by SARS-CoV-2 which is one of the coronaviruses. Realizing the severity of outcomes associated with this disease and its high rate of transmission, dentists were instructed by regulatory authorities, such as the American Dental Association, to stop providing treatment to dental patients except those who have emergency complaints. This was mainly for protection of dental healthcare personnel, their families, contacts, and their patients from the transmission of virus, and also to preserve the much-needed supplies of personal protective equipment (PPE). Dentists at all times should competently follow cross-infection control protocols, but particularly during this critical time, they should do their best to decide on the emergency cases that are indicated for dental treatment. Dentists should also be updated on how this pandemic is related to their profession in order to be well oriented and prepared. This overview will address several issues concerned with the COVID-19 pandemic that directly relate to dental practice in terms of prevention, treatment, and orofacial clinical manifestations.
Collapse
|
|
17
|
Lyu X, Zeng L, Zhang H, Ke Y, Liu X, Zhao N, Yuan J, Chen G, Yang S. Hydroxychloroquine suppresses lung tumorigenesis via inducing FoxO3a nuclear translocation through STAT3 inactivation. Life Sci 2020; 246:117366. [PMID: 32001266 DOI: 10.1016/j.lfs.2020.117366] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 01/09/2020] [Accepted: 01/26/2020] [Indexed: 10/25/2022]
Abstract
BACKGROUND Hydroxychloroquine exhibits synergistic anticancer properties as an adjuvant. However, the role and molecular mechanisms underlying of HCQ as monotherapy for lung adenocarcinoma (LUAD) have yet to be elucidated. METHODS We assessed the antitumor effects of HCQ in LUAD cells through a series of in vitro and in vivo assays. GEO database and R packages were used to predict molecular mechanisms of HCQ in the treatment of lung adenocarcinoma, followed by verification of gene expression and subcellular localization via immunoblotting, immunofluorescent and immunohistochemistry assays. RESULTS We showed the phenotypic effects that HCQ inhibited cell growth, induced apoptosis and cell cycle arrest at G1/S transition in A549 and PC-9 cells, which was associated with inhibition of CDK2, CDK4, CyclinD1 and CyclinE, but up-regulation of p21 and p27Kip1. Bioinformatic analysis predicted that 63 targets related to HCQ and LUAD were mainly enriched in JAK-STAT and FoxO pathways. Then, we observed that HCQ decreased the phosphorylation of STAT3, but increased the expression of FoxO3a and its accumulation in the nucleus. The specific STAT3 inhibitor cryptotanshinon augmented the HCQ-induced upregulation and nuclear translocation of FoxO3a. In addition, HCQ increased the expression of p27Kip1, which was impaired by FoxO3a blockade with siRNA. Finally, ablation of p27Kip1 expression abrogated the cytotoxicity of HCQ. More importantly, similar results were further confirmed in vivo. CONCLUSIONS Taken together, this study suggests that STAT3/FoxO3a/p27Kip1 signaling pathway is involved in the anticancer effects of HCQ, and provides preliminary evidence for therapeutic prospects of HCQ alone in LUAD.
Collapse
Affiliation(s)
- Xin Lyu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China
| | - Lizhong Zeng
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China
| | - Hua Zhang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China
| | - Yue Ke
- Department of Radiation Oncology, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China
| | - Xuan Liu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China
| | - Nannan Zhao
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China
| | - Jingyan Yuan
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China
| | - Guoan Chen
- School of Medicine, Southern University of Science and Technology, No. 1088, Xueyuan Road, Nanshan District, Shenzhen 518055, Guangdong, China
| | - Shuanying Yang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an 710004, Shaanxi, PR China.
| |
Collapse
|
|
18
|
Li Q, Dong H, Yang G, Song Y, Mou Y, Ni Y. Mouse Tumor-Bearing Models as Preclinical Study Platforms for Oral Squamous Cell Carcinoma. Front Oncol 2020; 10:212. [PMID: 32158692 PMCID: PMC7052016 DOI: 10.3389/fonc.2020.00212] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 02/06/2020] [Indexed: 12/16/2022] Open
Abstract
Preclinical animal models of oral squamous cell carcinoma (OSCC) have been extensively studied in recent years. Investigating the pathogenesis and potential therapeutic strategies of OSCC is required to further progress in this field, and a suitable research animal model that reflects the intricacies of cancer biology is crucial. Of the animal models established for the study of cancers, mouse tumor-bearing models are among the most popular and widely deployed for their high fertility, low cost, and molecular and physiological similarity to humans, as well as the ease of rearing experimental mice. Currently, the different methods of establishing OSCC mouse models can be divided into three categories: chemical carcinogen-induced, transplanted and genetically engineered mouse models. Each of these methods has unique advantages and limitations, and the appropriate application of these techniques in OSCC research deserves our attention. Therefore, this review comprehensively investigates and summarizes the tumorigenesis mechanisms, characteristics, establishment methods, and current applications of OSCC mouse models in published papers. The objective of this review is to provide foundations and considerations for choosing suitable model establishment methods to study the relevant pathogenesis, early diagnosis, and clinical treatment of OSCC.
Collapse
Affiliation(s)
- Qiang Li
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Heng Dong
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- Department of Oral Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Guangwen Yang
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yuxian Song
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yongbin Mou
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- Department of Oral Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- *Correspondence: Yongbin Mou
| | - Yanhong Ni
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- Yanhong Ni
| |
Collapse
|
|
19
|
Cirone M, Gilardini Montani MS, Granato M, Garufi A, Faggioni A, D'Orazi G. Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:262. [PMID: 31200739 PMCID: PMC6570888 DOI: 10.1186/s13046-019-1275-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 06/10/2019] [Indexed: 12/14/2022]
Abstract
Autophagy is a catabolic process whose activation may help cancer cells to adapt to cellular stress although, in some instances, it can induce cell death. Autophagy stimulation or inhibition has been considered an opportunity to treat cancer, especially in combination with anticancer therapies, although autophagy manipulation may be viewed as controversial. Thus, whether to induce or to inhibit autophagy may be the best option in the different cancer patients is still matter of debate. Her we will recapitulate the possible advantages or disadvantages of manipulating autophagy in cancer, not only with the aim to obtain cancer cell death and disable oncogenes, but also to evaluate its interplay with the immune response which is fundamental for the success of anticancer therapies.
Collapse
Affiliation(s)
- Mara Cirone
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy. .,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.
| | - Maria Saveria Gilardini Montani
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Marisa Granato
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Alessia Garufi
- Department of Medical Science, University 'G. D'Annunzio', 66013, Chieti, Italy.,Department of Research, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Alberto Faggioni
- Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy.,Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Gabriella D'Orazi
- Department of Medical Science, University 'G. D'Annunzio', 66013, Chieti, Italy. .,Department of Research, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy.
| |
Collapse
|
|
20
|
Improving Encapsulation of Hydrophilic Chloroquine Diphosphate into Biodegradable Nanoparticles: A Promising Approach against Herpes Virus Simplex-1 Infection. Pharmaceutics 2018; 10:pharmaceutics10040255. [PMID: 30513856 PMCID: PMC6320969 DOI: 10.3390/pharmaceutics10040255] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/24/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Chloroquine diphosphate (CQ) is a hydrophilic drug with low entrapment efficiency in hydrophobic nanoparticles (NP). Herpes simplex virus type 1 (HSV-1) is an enveloped double-stranded DNA virus worldwide known as a common human pathogen. This study aims to develop chloroquine-loaded poly(lactic acid) (PLA) nanoparticles (CQ-NP) to improve the chloroquine anti- HSV-1 efficacy. CQ-NP were successfully prepared using a modified emulsification-solvent evaporation method. Physicochemical properties of the NP were monitored using dynamic light scattering, atomic force microscopy, drug loading efficiency, and drug release studies. Spherical nanoparticles were produced with modal diameter of <300 nm, zeta potential of −20 mv and encapsulation efficiency of 64.1%. In vitro assays of CQ-NP performed in Vero E6 cells, using the MTT-assay, revealed different cytotoxicity levels. Blank nanoparticles (B-NP) were biocompatible. Finally, the antiviral activity tested by the plaque reduction assay revealed greater efficacy for CQ-NP compared to CQ at concentrations equal to or lower than 20 µg mL−1 (p < 0.001). On the other hand, the B-NP had no antiviral activity. The CQ-NP has shown feasible properties and great potential to improve the antiviral activity of drugs.
Collapse
|
|
21
|
Avniel-Polak S, Leibowitz G, Doviner V, Gross DJ, Grozinsky-Glasberg S. Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model. Endocr Relat Cancer 2018; 25:677-686. [PMID: 29636368 DOI: 10.1530/erc-18-0121] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.
Collapse
Affiliation(s)
- Shani Avniel-Polak
- Neuroendocrine Tumor LaboratoryEndocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Gil Leibowitz
- Neuroendocrine Tumor LaboratoryEndocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Victoria Doviner
- Department of PathologyShaare Zedek Medical Center, Jerusalem, Israel
| | - David J Gross
- Neuroendocrine Tumor LaboratoryEndocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Simona Grozinsky-Glasberg
- Neuroendocrine Tumor LaboratoryEndocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| |
Collapse
|
|
22
|
Lin F, Gao L, Su Z, Cao X, Zhan Y, Li Y, Zhang B. Knockdown of KPNA2 inhibits autophagy in oral squamous cell carcinoma cell lines by blocking p53 nuclear translocation. Oncol Rep 2018; 40:179-194. [PMID: 29781035 PMCID: PMC6059741 DOI: 10.3892/or.2018.6451] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 05/10/2018] [Indexed: 02/07/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC), one of the 10 most common types of neoplasms in the US, constitutes ~90% of all cases of oral malignancies. Chemoresistance and metastasis are difficult to avoid during the course of treatment, leading to a poor prognosis and a high mortality rate for patients with OSCC. Autophagy, a critical conserved cellular process, has been reported to be highly associated with the regulation of chemoresistance and metastasis of cancer cells. The present study investigated the role of karyopherin α2 (KPNA2), a member of the importin α family, which may serve an important role in p53 nucleocytoplasmic transport in the process of OSCC autophagy. In the CAL-27, SCC-15 and Tca8113 OSCC cell lines, we observed that the downregulation of KPNA2 suppressed cell migration and cisplatin resistance, using wound-healing, Transwell and CCK-8 assays. Additionally, the results of western blot analysis and transmission electron microscopy (TEM) analysis indicated that the knockdown of KPNA2 inhibited autophagy. We confirmed that the inhibition of autophagy with anti-autophagy agents decreased the migration and cisplatin resistance of OSCC cells. We hypothesized that the suppression of cell migration and cisplatin resistance induced by KPNA2 knockdown may be associated with the inhibition of autophagy. To identify the underlying mechanism, further experiments determined that KPNA2 affects the level of autophagy via regulating the p53 nuclear import. Thus, the present study demonstrated that the function of KPNA2 in the process of autophagy may be p53-dependent, and by regulating the translocation of p53, KPNA2 can support autophagy to promote the chemoresistance and metastasis of OSCC cells.
Collapse
Affiliation(s)
- Feng Lin
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Li Gao
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhenyu Su
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Xiaofang Cao
- Department of Dentistry, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yuanbo Zhan
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Ying Li
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Bin Zhang
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| |
Collapse
|