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Tatsumi Y, Masuda T, Watanabe T, Utomo RY, Zulfin UM, Meiyanto E, Ozaki T, Suenaga Y, Kamikubo Y. Antitumor effect of curcumin analog on osteosarcoma through the inhibition of p300‑mediated histone acetylation. Oncol Rep 2025; 53:47. [PMID: 39981920 DOI: 10.3892/or.2025.8880] [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: 10/11/2024] [Accepted: 01/29/2025] [Indexed: 02/22/2025] Open
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Histone acetyltransferases (HATs), such as p300, CBP and PCAF, modulate numerous biological processes, including cellular proliferation and oncogenesis, through histone acetylation. In the present study, it was investigated whether the curcumin analogs such as pentagamavunon‑1 (PGV‑1) and chemoprevention curcumin analog‑1.1 (CCA‑1.1) could target p300 and suppress OS. Computational analysis indicated that PGV‑1 and CCA‑1.1 bind to the HAT domain of p300. Accordingly, these analogs efficiently inhibited the HAT activity of p300 in vitro and promoted OS cell apoptosis, accompanied by downregulation of acetylated histone H3 at Lys‑27 and phosphorylated oncogenic STAT3 at Tyr‑705. Finally, it was found that PGV‑1 and CCA‑1.1 but not PGV‑1, significantly attenuates the growth of OS developed on the chicken egg chorioallantoic membrane (CAM). Collectively, the present results strongly suggest that curcumin analog‑mediated targeting of p300 might provide a clue to develop an effective treatment strategy against patients with OS.
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Affiliation(s)
- Yasutoshi Tatsumi
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Tatsuya Masuda
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Takayoshi Watanabe
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Rohmad Yudi Utomo
- Macromolecular Engineering Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Ummi Maryam Zulfin
- Macromolecular Engineering Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Edy Meiyanto
- Macromolecular Engineering Laboratory, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Toshinori Ozaki
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Yusuke Suenaga
- Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
| | - Yasuhiko Kamikubo
- Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260‑8717, Japan
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2
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Alalhareth IS, Alyami SM, Alshareef AH, Ajeibi AO, Al Munjem MF, Elfifi AA, Alsharif MM, Alzahrani SA, Alqaad MA, Bakir MB, Abdel-Wahab BA. Cellular Epigenetic Targets and Epidrugs in Breast Cancer Therapy: Mechanisms, Challenges, and Future Perspectives. Pharmaceuticals (Basel) 2025; 18:207. [PMID: 40006021 PMCID: PMC11858621 DOI: 10.3390/ph18020207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 01/31/2025] [Accepted: 02/01/2025] [Indexed: 02/27/2025] Open
Abstract
Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering potential new diagnostic and prognostic markers, treatment efficacy predictors, and therapeutic agents. Key modifications include DNA cytosine methylation and the covalent modification of histone proteins. Unlike genetic mutations, reprogramming the epigenetic landscape of the cancer epigenome is a promising targeted therapy for the treatment and reversal of drug resistance. Epidrugs, which target DNA methylation and histone modifications, can provide novel options for the treatment of breast cancer by reversing the acquired resistance to treatment. Currently, the most promising approach involves combination therapies consisting of epidrugs with immune checkpoint inhibitors. This review examines the aberrant epigenetic regulation of breast cancer initiation and progression, focusing on modifications related to estrogen signaling, drug resistance, cancer progression, and the epithelial-mesenchymal transition (EMT). It examines existing epigenetic drugs for treating breast cancer, including agents that modify DNA, inhibitors of histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone demethyltransferases. It also delves into ongoing studies on combining epidrugs with other therapies and addresses the upcoming obstacles in this field.
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Affiliation(s)
- Ibrahim S. Alalhareth
- College of Pharmacy, Najran University, Najran 66256, Saudi Arabia; (I.S.A.); (S.M.A.)
| | - Saleh M. Alyami
- College of Pharmacy, Najran University, Najran 66256, Saudi Arabia; (I.S.A.); (S.M.A.)
| | - Ali H. Alshareef
- Department of Pharmaceuticals Care, Ministry of Defense, Najran 66281, Saudi Arabia; (A.H.A.); (A.O.A.); (A.A.E.); (M.M.A.)
| | - Ahmed O. Ajeibi
- Department of Pharmaceuticals Care, Ministry of Defense, Najran 66281, Saudi Arabia; (A.H.A.); (A.O.A.); (A.A.E.); (M.M.A.)
| | - Manea F. Al Munjem
- King Khaled Hospital -Najran Health Cluster, Najran 66261, Saudi Arabia;
| | - Ahmad A. Elfifi
- Department of Pharmaceuticals Care, Ministry of Defense, Najran 66281, Saudi Arabia; (A.H.A.); (A.O.A.); (A.A.E.); (M.M.A.)
| | - Meshal M. Alsharif
- Department of Pharmaceuticals Care, Ministry of Defense, Najran 66281, Saudi Arabia; (A.H.A.); (A.O.A.); (A.A.E.); (M.M.A.)
| | - Seham A. Alzahrani
- Pharmacy Department, Khamis Mushait General Hospital, King Khalid Rd, Al Shifa, Khamis Mushait 62433, Saudi Arabia;
| | - Mohammed A. Alqaad
- Department of Pharmaceutical Care Services, Al Noor Specialized Hospital, Makkah Health, Cluster, Makkah 24241, Saudi Arabia;
| | - Marwa B. Bakir
- Department of Medical Education, College of Medicine, Najran University, Najran 1988, Saudi Arabia;
| | - Basel A. Abdel-Wahab
- Department of Pharmacology, College of Pharmacy, Najran University, Najran 1988, Saudi Arabia
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Gronkowska K, Robaszkiewicz A. Genetic dysregulation of EP300 in cancers in light of cancer epigenome control - targeting of p300-proficient and -deficient cancers. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200871. [PMID: 39351073 PMCID: PMC11440307 DOI: 10.1016/j.omton.2024.200871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Some cancer types including bladder, cervical, and uterine cancers are characterized by frequent mutations in EP300 that encode histone acetyltransferase p300. This enzyme can act both as a tumor suppressor and oncogene. In this review, we describe the role of p300 in cancer initiation and progression regarding EP300 aberrations that have been identified in TGCA Pan-Cancer Atlas studies and we also discuss possible anticancer strategies that target EP300 mutated cancers. Copy number alterations, truncating mutations, and abnormal EP300 transcriptions that affect p300 abundance and activity are associated with several pathological features such as tumor grading, metastases, and patient survival. Elevated EP300 correlates with a higher mRNA level of other epigenetic factors and chromatin remodeling enzymes that co-operate with p300 in creating permissive conditions for malignant transformation, tumor growth and metastases. The status of EP300 expression can be considered as a prognostic marker for anticancer immunotherapy efficacy, as EP300 mutations are followed by an increased expression of PDL-1.HAT activators such as CTB or YF2 can be applied for p300-deficient patients, whereas the natural and synthetic inhibitors of p300 activity, as well as dual HAT/bromodomain inhibitors and the PROTAC degradation of p300, may serve as strategies in the fight against p300-fueled cancers.
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Affiliation(s)
- Karolina Gronkowska
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
- Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland
| | - Agnieszka Robaszkiewicz
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
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Pathikonda S, Amirmahani F, Mathew D, Muthukrishnan SD. Histone acetyltransferases as promising therapeutic targets in glioblastoma resistance. Cancer Lett 2024; 604:217269. [PMID: 39326554 DOI: 10.1016/j.canlet.2024.217269] [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: 06/17/2024] [Revised: 09/14/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024]
Abstract
Glioblastoma (GBM) is a fatal adult brain tumor with an extremely poor prognosis. GBM poses significant challenges for targeted therapies due to its intra- and inter-tumoral heterogeneity, a highly immunosuppressive microenvironment, diffuse infiltration into normal brain parenchyma, protection by the blood-brain barrier and acquisition of therapeutic resistance. Recent studies have implicated epigenetic modifiers as key players driving tumorigenesis, resistance, and progression of GBM. While the vast majority of GBM research on epigenetic modifiers thus far has focused predominantly on elucidating the functional roles and targeting of DNA methyltransferases and histone deacetylases, emerging evidence indicates that histone acetyltransferases (HATs) also play a key role in mediating plasticity and therapeutic resistance in GBM. Here, we will provide an overview of HATs, their dual roles and functions in cancer as both tumor suppressors and oncogenes and focus specifically on their implications in GBM resistance. We also discuss the technical challenges in developing selective HAT inhibitors and highlight their promise as potential anti-cancer therapeutics for treating intractable cancers such as GBM.
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Affiliation(s)
- Spoorthy Pathikonda
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
| | - Farzaneh Amirmahani
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
| | - Diya Mathew
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
| | - Sree Deepthi Muthukrishnan
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
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Al Azzani M, Nizami ZN, Magramane R, Sekkal MN, Eid AH, Al Dhaheri Y, Iratni R. Phytochemical-mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach. Phytother Res 2024; 38:4353-4385. [PMID: 38961675 DOI: 10.1002/ptr.8283] [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: 01/20/2024] [Revised: 05/30/2024] [Accepted: 06/13/2024] [Indexed: 07/05/2024]
Abstract
Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are crossed. The pro-survival aspects of these processes are exploited by cancer cells for tumor development and progression. Therefore, anticancer drugs targeting autophagy or ER stress to induce cell death and/or block the pro-survival aspects are being investigated extensively. Consistently, several phytochemicals have been reported to exert their anticancer effects by modulating autophagy and/or ER stress. Various phytochemicals (e.g., celastrol, curcumin, emodin, resveratrol, among others) activate the unfolded protein response to induce ER stress-mediated apoptosis through different pathways. Similarly, various phytochemicals induce autophagy through different mechanisms (namely mechanistic target of Rapamycin [mTOR] inhibition). However, phytochemical-induced autophagy can function either as a cytoprotective mechanism or as programmed cell death type II. Interestingly, at times, the same phytochemical (e.g., 6-gingerol, emodin, shikonin, among others) can induce cytoprotective autophagy or programmed cell death type II depending on cellular contexts, such as cancer type. Although there is well-documented mechanistic interplay between autophagy and ER stress, only a one-way modulation was noted with some phytochemicals (carnosol, capsaicin, cryptotanshinone, guangsangon E, kaempferol, and δ-tocotrienol): ER stress-dependent autophagy. Plant extracts are sources of potent phytochemicals and while numerous phytochemicals have been investigated in preclinical and clinical studies, the search for novel phytochemicals with anticancer effects is ongoing from plant extracts used in traditional medicine (e.g., Origanum majorana). Nonetheless, the clinical translation of phytochemicals, a promising avenue for cancer therapeutics, is hindered by several limitations that need to be addressed in future studies.
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Affiliation(s)
- Mazoun Al Azzani
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Zohra Nausheen Nizami
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Rym Magramane
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohammed N Sekkal
- Department of Surgery, Specialty Orthopedic, Tawam Hospital, Al Ain, United Arab Emirates
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Yusra Al Dhaheri
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
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6
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S PR, Banerjee R, Drummond CJ, Conn CE. Permanently Charged Cationic Lipids-Evolution from Excipients to Therapeutic Lipids. SMALL SCIENCE 2024; 4:2300270. [PMID: 40212121 PMCID: PMC11935225 DOI: 10.1002/smsc.202300270] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 04/28/2024] [Indexed: 04/13/2025] Open
Abstract
Cationic lipids are crucial in medical and biotechnological applications including cellular transfection and gene delivery. Ionizable cationic lipids are critical components of the mRNA-based COVID vaccines while permanently charged cationic lipids have shown promise in cancer treatment. Despite significant research progress over the past few decades in designing improved, biocompatible cationic lipids, their transfection efficiency remains lower than that of viral vectors. Cationic lipids with additional functionalities like fusogenicity, stimuli-responsiveness, targeting capabilities, and therapeutic activity have been engineered to improve their performance. This review highlights the importance of molecular hybridization toward the design of biocompatible cationic lipids having fusogenic, stimuli-responsive, targeting, or therapeutic properties. This review mainly focuses on cationic lipids, having a permanent positive charge in the headgroup region, as these are typically employed to both increase cellular interactions and for improved loading, particularly for anionic nucleic acid-based therapeutics and vaccines. Structure-activity relationships between the lipid chemical structure (headgroup, spacer, hydrocarbon chain) and, to a lesser extent, the self-assembled nanostructure and the intrinsic biological activity of the multi-functional cationic lipids are described. Finally, the challenges involved in developing smart lipids without affecting their inherent capacity to self-assemble into structured nano-carriers are discussed.
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Affiliation(s)
- Pushpa Ragini S
- Academy of Scientific and Innovation Research (AcSIR)Ghaziabad201002India
- Department of Oils, Lipid Science and TechnologyCSIR‐Indian Institute of Chemical TechnologyHyderabad500 007India
- School of ScienceSTEM CollegeRMIT University124 La Trobe StreetMelbourneVIC3000Australia
| | - Rajkumar Banerjee
- Academy of Scientific and Innovation Research (AcSIR)Ghaziabad201002India
- Department of Oils, Lipid Science and TechnologyCSIR‐Indian Institute of Chemical TechnologyHyderabad500 007India
| | - Calum J. Drummond
- School of ScienceSTEM CollegeRMIT University124 La Trobe StreetMelbourneVIC3000Australia
| | - Charlotte E. Conn
- School of ScienceSTEM CollegeRMIT University124 La Trobe StreetMelbourneVIC3000Australia
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Lei YH, Tang Q, Ni Y, Li CH, Luo P, Huang K, Chen X, Zhu YX, Wang NY. Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders. Bioorg Chem 2024; 148:107427. [PMID: 38728911 DOI: 10.1016/j.bioorg.2024.107427] [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: 03/14/2024] [Revised: 04/22/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024]
Abstract
Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.
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Affiliation(s)
- Yan-Hua Lei
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Qing Tang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Yang Ni
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Cai-Hua Li
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Peng Luo
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Kun Huang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Xin Chen
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China
| | - Yong-Xia Zhu
- Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology, Chengdu, China.
| | - Ning-Yu Wang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China.
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8
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Dai Q, Yuan Z, Sun Q, Ao Z, He B, Jiang Y. Discovery of novel nucleoside derivatives as selective lysine acetyltransferase p300 inhibitors for cancer therapy. Bioorg Med Chem Lett 2024; 104:129742. [PMID: 38604299 DOI: 10.1016/j.bmcl.2024.129742] [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: 11/28/2023] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
P300 and CBP are two closely related histone acetyltransferases that are important transcriptional coactivators of many cellular processes. Inhibition of the transcriptional regulator p300/CBP is a promising therapeutic approach in oncology. However, there are no reported single selective p300 or CBP inhibitors to date. In this study, we designed and optimized a series of lysine acetyltransferase p300 selective inhibitors bearing a nucleoside scaffold. Most compounds showed excellent inhibitory activity against p300 with IC50 ranging from 0.18 to 9.90 μM, except for J16, J29, J40, and J48. None of the compounds showed inhibitory activity against CBP (inhibition rate < 50 % at 10 µM). Then the cytotoxicity of the compounds against a series of cancer cells were evaluated. Compounds J31 and J32 showed excellent proliferation inhibitory activity on cancer cells T47D and H520 with desirable selectivity profile of p300 over CBP. These compounds could be promising lead compounds for the development of novel epigenetic inhibitors as antitumor agents.
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Affiliation(s)
- Qiuzi Dai
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China
| | - Zigao Yuan
- Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China
| | - Qinsheng Sun
- Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China
| | - Zhuolin Ao
- Division of Biosciences, Department of Biochemistry, University College London, London WC1E6AA, UK
| | - Binsheng He
- The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China.
| | - Yuyang Jiang
- Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China; State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
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Zhao PW, Cui JX, Wang XM. Upregulation of p300 in paclitaxel-resistant TNBC: implications for cell proliferation via the PCK1/AMPK axis. THE PHARMACOGENOMICS JOURNAL 2024; 24:5. [PMID: 38378770 DOI: 10.1038/s41397-024-00324-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/18/2024] [Accepted: 01/24/2024] [Indexed: 02/22/2024]
Abstract
OBJECTIVE To explore the role of p300 in the context of paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) cells, focusing on its interaction with the phosphoenolpyruvate carboxykinase 1 (PCK1)/adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS The expression of p300 and PCK1 at the messenger ribonucleic acid (mRNA) level was detected using a quantitative polymerase chain reaction. The GeneCards and GEPIA databases were used to investigate the relationship between p300 and PCK1. The MDA-MB-231/PTX cell line, known for its PTX resistance, was chosen to understand the specific role of p300 in such cells. The Lipofectamine™ 3000 reagent was used to transfer the p300 small interfering RNA and the overexpression of PCK1 plasmid into MDA-MB-231/PTX. The expression levels of p300, PCK1, 5'AMPK and phosphorylated AMPK (p-AMPK) were determined using the western blot test. RESULTS In TNBC cancer tissue, the expression of p300 was increased compared with TNBC paracancerous tissue (P < 0.05). In the MDA-MB-231 cell line of TNBC, the expression of p300 was lower than in the PTX-resistant TNBC cells (MDA-MB-231/PTX) (P < 0.05). The PCK1 expression was decreased in the TNBC cancer tissue compared with TNBC paracancerous tissue, and the PCK1 expression was reduced in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05) indicating that PCK1 was involved in the resistance function. Additionally, p-AMPK was decreased in MDA-MB-231/PTX compared with MDA-MB-231 (P < 0.05). The adenosine triphosphate (ATP) level was also detected and was significantly lower in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05). Additionally, cell proliferation increased significantly in MDA-MB-231/PTX at 48 and 72 h (P < 0.05) suggesting that MDA-MB-231/PTX cells obtained the resistance function which was associated with AMPK and ATP level. When p300 was inhibited, p-AMPK and ATP levels elevated in MDA-MB-231/PTX (P < 0.05). When PCK1 was suppressed, the ATP consumption rate decreased, and cell proliferation increased (P < 0.05). However, there were no changes in p300. CONCLUSIONS In MDA-MB-231/PTX, p300 can inhibit p-AMPK and ATP levels by inhibiting PCK1 expression. Our findings suggest that targeting p300 could modulate the PCK1/AMPK axis, offering a potential therapeutic avenue for overcoming PTX resistance in TNBC.
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Affiliation(s)
- Peng-Wei Zhao
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, No.5 Xinhua Street, Huimin District, Hohhot, 010059, China
| | - Jia-Xian Cui
- Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, No.5 Xinhua Street, Huimin District, Hohhot, 010059, China
| | - Xiu-Mei Wang
- Medical Oncology, Affiliated Cancer Hospital of Inner Mongolia Medical University, No. 42 Zhaowuda Road, Saihan District, Hohhot, 010020, Inner Mongolia, China.
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Jramne-Saleem Y, Danilenko M. Roles of Glutathione and AP-1 in the Enhancement of Vitamin D-Induced Differentiation by Activators of the Nrf2 Signaling Pathway in Acute Myeloid Leukemia Cells. Int J Mol Sci 2024; 25:2284. [PMID: 38396960 PMCID: PMC10889780 DOI: 10.3390/ijms25042284] [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: 12/24/2023] [Revised: 02/04/2024] [Accepted: 02/10/2024] [Indexed: 02/25/2024] Open
Abstract
Active vitamin D derivatives (VDDs)-1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs-are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells restored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1.
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Affiliation(s)
| | - Michael Danilenko
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel;
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Grover P, Thakur K, Bhardwaj M, Mehta L, Raina SN, Rajpal VR. Phytotherapeutics in Cancer: From Potential Drug Candidates to Clinical Translation. Curr Top Med Chem 2024; 24:1050-1074. [PMID: 38279745 DOI: 10.2174/0115680266282518231231075311] [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: 09/15/2023] [Revised: 11/27/2023] [Accepted: 12/05/2023] [Indexed: 01/28/2024]
Abstract
Annually, a significant number of individuals succumb to cancer, an anomalous cellular condition characterized by uncontrolled cellular proliferation and the emergence of highly perilous tumors. Identifying underlying molecular mechanism(s) driving disease progression has led to various inventive therapeutic approaches, many of which are presently under pre-clinical and/or clinical trials. Over the recent years, numerous alternative strategies for addressing cancer have also been proposed and put into practice. This article delineates the modern therapeutic drugs employed in cancer treatment and their associated toxicity. Due to inherent drug toxicity associated with most modern treatments, demand rises for alternative therapies and phytochemicals with minimal side effects and proven efficacy against cancer. Analogs of taxol, Vinca alkaloids like vincristine and vinblastine, and podophyllotoxin represent a few illustrative examples in this context. The phytochemicals often work by modifying the activity of molecular pathways that are thought to be involved in the onset and progression of cancer. The principal objective of this study is to provide an overview of our current understanding regarding the pharmacologic effects and molecular targets of the active compounds found in natural products for cancer treatment and collate information about the recent advancements in this realm. The authors' interest in advancing the field of phytochemical research stems from both the potential of these compounds for use as drugs as well as their scientific validity. Accordingly, the significance of herbal formulations is underscored, shedding light on anticancer phytochemicals that are sought after at both pre-clinical and clinical levels, with discussion on the opportunities and challenges in pre-clinical and clinical cancer studies.
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Affiliation(s)
- Parul Grover
- KIET School of Pharmacy, KIET Group of Institutions, Delhi-NCR, Ghaziabad, 201206, India
| | | | - Monika Bhardwaj
- Natural Product and Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR-IIIM), Jammu, 180001, India
| | - Lovekesh Mehta
- Amity Institute of Pharmacy, Amity University, Noida, 201301, India
| | - Soom Nath Raina
- Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, Noida, 201301, India
| | - Vijay Rani Rajpal
- Department of Botany, Hansraj College, Delhi University, Delhi, 110007, India
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12
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Hosseini A, Ghorbani A, Alavi MS, Forouhi N, Rajabian A, Boroumand-Noughabi S, Sahebkar A, Eid AH. Cardioprotective effect of Sanguisorba minor against isoprenaline-induced myocardial infarction in rats. Front Pharmacol 2023; 14:1305816. [PMID: 38223198 PMCID: PMC10784747 DOI: 10.3389/fphar.2023.1305816] [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: 10/02/2023] [Accepted: 11/27/2023] [Indexed: 01/16/2024] Open
Abstract
Introduction: Oxidative stress is a major instigator of various cardiovascular diseases, including myocardial infarction (MI). Despite available drugs, there is still an increased need to look for alternative therapies or identify new bioactive compounds. Sanguisorba minor (S. minor) is a native herb characterized by its potent antioxidant activity. This study was designed to evaluate the effect of S. minor against isoprenaline-induced MI. Methods: Rats were treated with the hydro-ethanolic extract of the aerial parts of S. minor at doses of 100 or 300 mg/kg orally for 9 days. Isoprenaline was injected subcutaneously at the dose of 85 mg/kg on days 8 and 9. Then, the activities of various cardiac injury markers including cardiac troponin (cTnT), lactate dehydrogenase (LDH), creatinine kinase muscle brain (CK-MB), creatinine phosphokinase (CPK), and antioxidant enzymes in serum were determined. Malondialdehyde (MDA) and thiol content were measured in cardiac tissue, and histopathological analysis was conducted. Results: Our results show that isoprenaline increased the serum levels of cTnT, LDH, CK-MB, and CPK (p < 0.001) and elevated MDA levels (p < 0.001) in cardiac tissue. Isoprenaline also reduced superoxide dismutase (SOD), catalase, and thiol content (p < 0.001). Importantly, the extract abolished isoprenaline-induced MI by elevating SOD and catalase (p < 0.001), reducing levels of MDA, and diminishing levels of cTnT, LDH, CK-MB, and CPK cardiac markers (p < 0.001). Histopathological studies of the cardiac tissue showed isoprenaline-induced injury that was significantly attenuated by the extract. Conclusion: Our results suggest that S. minor could abrogate isoprenaline-induced cardiac toxicity due to its ability to mitigate oxidative stress.
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Affiliation(s)
- Azar Hosseini
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Atieh Ghorbani
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohaddeseh Sadat Alavi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Forouhi
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arezoo Rajabian
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Science, Mashhad, Iran
| | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali H. Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
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Zhang Y, Zhang J, Li M, Qiao Y, Wang W, Ma L, Liu K. Target discovery of bioactive natural products with native-compound-coupled CNBr-activated Sepharose 4B beads (NCCB): Applications, mechanisms and outlooks. Bioorg Med Chem 2023; 96:117483. [PMID: 37951136 DOI: 10.1016/j.bmc.2023.117483] [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: 07/23/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 11/13/2023]
Abstract
Natural products (NPs) represent a treasure trove for drug discovery and development due to their chemical structural diversity and a broad spectrum of biological activities. Uncovering the biological targets and understanding their molecular mechanism of actions are crucial steps in the development of clinical therapeutics. However, the structural complexity of NPs and intricate nature of biological system present formidable challenges in target identification of NPs. Although significant advances have been made in the development of new chemical tools, these methods often require high levels of synthetic skills for preparing chemical probes. This can be costly and time-consuming relaying on operationally complicated procedures and instruments. In recent efforts, we and others have successfully developed an operationally simple and practical chemical tool known as native-compound-coupled CNBr-activated Sepharose 4B beads (NCCB) for NP target identification. In this approach, a native compound readily reacts with commercial CNBr-activated Sepharose 4B beads with a process that is easily performed in any biology laboratory. Based on NCCB, our group has identified the direct targets of more than 60 NPs. In this review, we will elucidate the application scopes, including flavonoids, quinones, terpenoids and others, characteristics, chemical mechanisms, procedures, advantages, disadvantages, and future directions of NCCB in specific target discovery.
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Affiliation(s)
- Yueteng Zhang
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Junjie Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Menglong Li
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Yan Qiao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Wei Wang
- Departments of Pharmacology & Toxicology and Chemistry & Biochemistry, and BIO5 Institute, University of Arizona, Tucson, AZ 85721, United States
| | - Lu Ma
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
| | - Kangdong Liu
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
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14
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Li A, Cao W. Downregulation of SODD mediates carnosol-induced reduction in cell proliferation in esophageal adenocarcinoma cells. Sci Rep 2023; 13:10580. [PMID: 37386230 PMCID: PMC10310760 DOI: 10.1038/s41598-023-37796-5] [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: 12/14/2022] [Accepted: 06/28/2023] [Indexed: 07/01/2023] Open
Abstract
Esophageal adenocarcinoma carries a poor prognosis associated with a 5-year survival rate of 12.5-20%. Therefore, a new therapeutic modality is needed for this lethal tumor. Carnosol is a phenolic diterpene purified from the herbs such as rosemary and Mountain desert sage and has been shown to have anticancer activities in multiple cancers. In this study we examined the effect of carnosol on cell proliferation in esophageal adenocarcinoma cells. We found that carnosol dose-dependently decreased cell proliferation in FLO-1 esophageal adenocarcinoma cells and significantly increased caspase-3 protein, indicating that carnosol decreases cell proliferation and increases cell apoptosis in FLO-1 cells. Carnosol significantly increased H2O2 production and N-acetyl cysteine, a reactive oxygen species (ROS) scavenger, significantly inhibited carnosol-induced decrease in cell proliferation, indicating that ROS may mediate carnosol-induced decrease in cell proliferation. Carnosol-induced decrease in cell proliferation was partially reversed by NADPH oxidase inhibitor apocynin, suggesting that NADPH oxidases may be partially involved in carnosol's effect. In addition, carnosol significantly downregulated SODD protein and mRNA expression and knockdown of SODD significantly inhibited the carnosol-induced reduction in cell proliferation, suggesting that downregulation of SODD may contribute to carnosol-induced reduction in cell proliferation. We conclude that carnosol dose-dependently decreased cell proliferation and significantly increased caspase-3 protein. Carnosol's effect may be through the overproduction of ROS and the downregulation of SODD. Carnosol might be useful for the treatment of esophageal adenocarcinoma.
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Affiliation(s)
- Aihua Li
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 593 Eddy St, APC12, Providence, RI, 02903, USA
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China
| | - Weibiao Cao
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 593 Eddy St, APC12, Providence, RI, 02903, USA.
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Chen J, Sun N, Li F, Li H, Tian J, Zheng S, Zhang L, Wang H, Luo Y. Carnosol Alleviates Collagen-Induced Arthritis by Inhibiting Th17-Mediated Immunity and Favoring Suppressive Activity of Regulatory T Cells. BIOMED RESEARCH INTERNATIONAL 2023; 2023:1179973. [PMID: 37415927 PMCID: PMC10322527 DOI: 10.1155/2023/1179973] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/22/2023] [Accepted: 06/05/2023] [Indexed: 07/08/2023]
Abstract
Current approaches are incurable for rheumatoid arthritis (RA). Regulatory T (Treg) cells and T helper cells (Th1 and Th17) are crucial in controlling the process of RA, which is characterized by inflammatory cell infiltration and bone destruction. Carnosol is an orthodiphenolic diterpene that has been extensively applied in traditional medicine for the treatment of multiple autoimmune and inflammatory diseases. Herein, we indicate that administration of carnosol dramatically alleviated the severity of collagen-induced arthritis (CIA) model with a decreased clinical score and inflammation reduction. Cellular mechanistically, carnosol inhibits the Th17 cell differentiation and maintains Treg cell suppressive function in vitro and in vivo. Meanwhile, it also restrains Treg cells from transdifferentiation into Th17 cells under inflammatory milieu. Furthermore, carnosol modulates the function of Th17 and Treg cells possibly via limiting IL-6R (CD126) expression. Collectively, our results suggest that carnosol can alleviate the severity of CIA via hiding Th17 cell differentiation and maintain the stability of Treg cells. Administration of carnosol can be applied as a potential therapy for patients with RA.
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Affiliation(s)
- Jun Chen
- The Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, 730000 Gansu, China
| | - Nianzhe Sun
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu, China
| | - Fuhan Li
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu, China
| | - Haolin Li
- Rheumatic Bone Disease Center, Gansu Provincial Hospital of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, 730000 Gansu, China
| | - Jiale Tian
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu, China
| | - Songguo Zheng
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Li Zhang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu, China
| | - Haidong Wang
- Rheumatic Bone Disease Center, Gansu Provincial Hospital of Traditional Chinese Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, 730000 Gansu, China
| | - Yang Luo
- The Department of Neurology, The First Hospital of Lanzhou University, Lanzhou, 730000 Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine, Lanzhou, 730000 Gansu, China
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16
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Alsamri H, Al Dhaheri Y, Iratni R. Targeting Triple-Negative Breast Cancer by the Phytopolyphenol Carnosol: ROS-Dependent Mechanisms. Antioxidants (Basel) 2023; 12:1349. [PMID: 37507889 PMCID: PMC10376170 DOI: 10.3390/antiox12071349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/29/2023] [Accepted: 06/01/2023] [Indexed: 07/30/2023] Open
Abstract
Triple-negative breast cancer (TNBC), which lacks the expression of the three hormone receptors (i.e., estrogen receptor, progesterone receptor, and human epidermal growth factor receptor), is characterized by a high proliferative index, high invasiveness, poor prognosis, early relapse, and a tendency to be present in advanced stages. These characteristics rank TNBC among the most aggressive and lethal forms of breast cancer. The lack of the three receptors renders conventional hormonal therapy ineffective against TNBC. Moreover, there are no clinically approved therapies that specifically target TNBC, and the currently used chemotherapeutic agents, such as cisplatin, taxanes, and other platinum compounds, have a limited clinical effect and develop chemoresistance over time. Phytochemicals have shown efficacy against several types of cancer, including TNBC, by targeting several pathways involved in cancer development and progression. In this review, we focus on one phytochemical carnosol, a natural polyphenolic terpenoid with strong anti-TNBC effects and its ROS-dependent molecular mechanisms of action. We discuss how carnosol targets key pathways and proteins regulating the cell cycle, growth, epigenetic regulators, invasion, and metastasis of TNBC. This review identifies carnosol as a potential novel targeting protein degradation molecule.
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Affiliation(s)
- Halima Alsamri
- General Requirement Department, Fatima College of Health Sciences, Al Ain P.O. Box 24162, United Arab Emirates
| | - Yusra Al Dhaheri
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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17
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Nizami ZN, Aburawi HE, Semlali A, Muhammad K, Iratni R. Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence. Antioxidants (Basel) 2023; 12:1159. [PMID: 37371889 DOI: 10.3390/antiox12061159] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/18/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Reactive oxygen species (ROS) are metabolic byproducts that regulate various cellular processes. However, at high levels, ROS induce oxidative stress, which in turn can trigger cell death. Cancer cells alter the redox homeostasis to facilitate protumorigenic processes; however, this leaves them vulnerable to further increases in ROS levels. This paradox has been exploited as a cancer therapeutic strategy with the use of pro-oxidative drugs. Many chemotherapeutic drugs presently in clinical use, such as cisplatin and doxorubicin, induce ROS as one of their mechanisms of action. Further, various drugs, including phytochemicals and small molecules, that are presently being investigated in preclinical and clinical studies attribute their anticancer activity to ROS induction. Consistently, this review aims to highlight selected pro-oxidative drugs whose anticancer potential has been characterized with specific focus on phytochemicals, mechanisms of ROS induction, and anticancer effects downstream of ROS induction.
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Affiliation(s)
- Zohra Nausheen Nizami
- Department of Biology, College of Science, United Arab Emirates University, Al Ain PO Box 15551, United Arab Emirates
| | - Hanan E Aburawi
- Department of Biology, College of Science, United Arab Emirates University, Al Ain PO Box 15551, United Arab Emirates
| | - Abdelhabib Semlali
- Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire-Université Laval, Quebec, QC G1V 0A6, Canada
| | - Khalid Muhammad
- Department of Biology, College of Science, United Arab Emirates University, Al Ain PO Box 15551, United Arab Emirates
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain PO Box 15551, United Arab Emirates
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18
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Liao F, Bao T, Tao G, Hu Y, Han C. In vitro evaluation of the composition and acaricidal efficacy of Urtica fissa leaf ethyl acetate extract against Sarcoptes scabiei mites. VET MED-CZECH 2023; 68:200-207. [PMID: 37982023 PMCID: PMC10581513 DOI: 10.17221/6/2023-vetmed] [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: 01/13/2023] [Accepted: 05/11/2023] [Indexed: 11/21/2023] Open
Abstract
In veterinary medicine, natural products provide an alternative to chemical agents for mite management. In the present study, the acaricidal efficacy of Urtica fissa leaf ethyl acetate extract against Sarcoptes scabiei mites was examined. The chemical composition of the extract was determined using liquid chromatography-mass spectrometry (LC-MS) analysis. The ethyl acetate extract was found to be extremely toxic to mites at a concentration of 100 mg/ml (m/v), killing all S. scabiei within two hours. The median lethal time (LT50) values for ethyl acetate extract concentrations of 25, 50, and 100 mg/ml against S. scabiei were 1.706, 1.204, and 0.750 h, respectively. The median lethal dosage (LC50) for S. scabiei was 19.14 mg/ml at two hours. The chemical composition of the ethyl acetate extract was evaluated using LC-MS, showing that the major components were schaftoside (8.259%), carnosol (6.736%), prostaglandin A2 (5.94%), 13(S)-HpOTrE (4.624%), nandrolone (4.264%), 1H-indole-3-carboxaldehyde (4.138%), 9-oxoODE (3.206%), and stearidonic acid (2.891%). In conclusion, these findings indicate that Urtica fissa contains promising new acaricidal compounds capable of successfully controlling animal mites.
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Affiliation(s)
- Fei Liao
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, P.R. China
- Guizhou Vocational College of Agriculture, Qingzhen, P.R. China
| | - Taotao Bao
- Qiandongnan Center for Animal Disease Control and Prevention, Kaili, Guizhou, P.R. China
| | - Guangyao Tao
- Guizhou Vocational College of Agriculture, Qingzhen, P.R. China
| | - Yanchun Hu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, P.R. China
| | - Changquan Han
- Guizhou Vocational College of Agriculture, Qingzhen, P.R. China
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Jaganathan R, Kumaradhas P. Binding mechanism of anacardic acid, carnosol and garcinol with PCAF: A comprehensive study using molecular docking and molecular dynamics simulations and binding free energy analysis. J Cell Biochem 2023; 124:731-742. [PMID: 36966470 DOI: 10.1002/jcb.30400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/09/2023] [Accepted: 03/12/2023] [Indexed: 03/27/2023]
Abstract
The p300/CBP associated factor bromodomain (PCAF Brd) is emerged as one of the promising target proteins for different types of cancers. PCAF is one among the histone acetyltransferase enzymes which involved in the regulation of transcriptase process by modifying the chromatin structure. Anacardic acid, carnosol, garcinol are the experimentally reported inhibitors of PCAF Brd; however, their detailed binding mechanism these inhibitors are not yet known. The intermolecular interaction, binding energy, and the stability of these inhibitors with the active site of PCAF Brd are playing the key role in the binding of these inhibitors with PCAF. The in silico study incorporates the molecular docking and dynamics simulations; these molecular level simulations allow to understand the binding mechanism. In the present study, the induced fit molecular docking and molecular dynamics of anacardic acid, carnosol and garcinol molecules against the PCAF Brd have been performed. The docking score values of these molecules are -5.112 (anacardic acid), -5.141 (carnosol), -5.199 (garcinol) and -3.641 (L45) kcal/mol, respectively. Further, the molecular dynamics simulation was carried out for these docked complexes to understand their conformational their stability and binding energy from the roots means square deviation (RMSD) and root means square of fluctuation (RMSF), and molecular mechanics with the generalized born and surface area solvation (MM/GBSA) binding free energy calculations. The intermolecular interactions and binding free energy values confirm that garcinol forms key interactions and has high binding affinity towards PCAF Brd on compare with the other two inhibitors. Therefore, garcinol may be considered as a potential inhibitor of PCAF Brd.
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Affiliation(s)
- Ramakrishnan Jaganathan
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
| | - Poomani Kumaradhas
- Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem, India
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20
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Liu M, Zhang K, Li Q, Pang H, Pan Z, Huang X, Wang L, Wu F, He G. Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors. J Med Chem 2023; 66:1678-1699. [PMID: 36695774 DOI: 10.1021/acs.jmedchem.2c01638] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In recent years, substantial research has been conducted on molecular mechanisms and inhibitors targeting bromodomains (BRDs) and extra-terminal (BET) family proteins. On this basis, non-BET BRD is gradually becoming a research hot spot. BRDs are abundant in histone acetyltransferase (HAT)-associated activating transcription factors, and BRD-containing HATs have been linked to cancer, inflammation, and viral replication. Therefore, the development of BRD-containing HATs as chemical probes is useful for understanding the specific biological roles of BRDs in diseases and drug discovery. Several types of BRD-containing HATs, including CBP/P300, PCAF/GCN5, and TAF1, are discussed in this context in terms of their structures, functions, and small-molecule inhibitors. Additionally, progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras in terms of drug design, biological activity, and disease application are summarized. These findings provide insights into the development of BRD inhibitors as potential drug candidates for various diseases.
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Affiliation(s)
- Mingxia Liu
- Department of Dermatology and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.,Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Kaiyao Zhang
- Department of Dermatology and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.,Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Qinjue Li
- West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Haiying Pang
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Zhaoping Pan
- Department of Dermatology and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Xiaowei Huang
- Department of Dermatology and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Lian Wang
- Department of Dermatology and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Fengbo Wu
- Department of Dermatology and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Gu He
- Department of Dermatology and Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China.,Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
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21
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Effect of rosemary addition on the sensorial and physicochemical qualities of dry-cured ham slices. Measurement of camphor transfer. Eur Food Res Technol 2023. [DOI: 10.1007/s00217-023-04209-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
AbstractThis study determined the effect of three concentrations (R1: high, R2: medium and R3: low) of rosemary added to dry-cured ham slices vacuum packaged. pH and the colour parameters were evaluated at 0, 7, 14, 28 and 60 days of storage; visual appearance, odour, flavour and camphor content were assessed at days 7, 14, 28 and 60. The rosemary concentration changed the colour parameters, significantly altering the visual appearance (p < 0.001 at 7 and 14 days; p < 0.5 at day 28), but did not affect the pH, neither odour nor flavour. Nevertheless, significant differences were found with the time on R1 and R2 in odour (p < 0.01 and p < 0.001, respectively) and in flavour (p < 0.001). Camphor content was similar in all samples but changed over the time in R1 (p < 0.001) and R2 (p < 0.01). In conclusion, despite the differences observed, it is evident that the addition of this spice was to the liking of the panellists, in any of the concentrations used.
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Du QC, Wang XY, Hu CK, Zhou L, Fu Z, Liu S, Wang J, Ma YY, Liu MY, Yu H. Integrative analysis of platelet-related genes for the prognosis of esophageal cancer. World J Clin Cases 2022; 10:12077-12088. [PMID: 36483802 PMCID: PMC9724514 DOI: 10.12998/wjcc.v10.i33.12077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 08/15/2022] [Accepted: 10/11/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Every year, esophageal cancer is responsible for 509000 deaths and around 572000 new cases worldwide. Although esophageal cancer treatment options have advanced, patients still have a dismal 5-year survival rate.
AIM To investigate the relationship between genes associated to platelets and the prognosis of esophageal cancer.
METHODS We searched differentially expressed genes for changes between 151 tumor tissues and 653 normal, healthy tissues using the “limma” package. To develop a prediction model of platelet-related genes, a univariate Cox regression analysis and least absolute shrinkage and selection operator Cox regression analysis were carried out. Based on a median risk score, patients were divided into high-risk and low-risk categories. A nomogram was created to predict the 1-, 2-, and 3-year overall survival (OS) of esophageal cancer patients using four platelet-related gene signatures, TNM stages, and pathological type. Additionally, the concordance index, receiver operating characteristic curve, and calibration curve were used to validate the nomogram.
RESULTS The prognosis of esophageal cancer was associated to APOOL, EP300, PLA2G6, and VAMP7 according to univariate Cox regression analysis and least absolute shrinkage and selection operator regression analysis. Patients with esophageal cancer at high risk had substantially shorter OS than those with cancer at low risk, according to a Kaplan-Meier analysis (P < 0.05). TNM stage (hazard ratio: 2.187, 95% confidence interval: 1.242-3.852, P = 0.007) in both univariate and multivariate Cox regression and risk score were independently correlated with OS (hazard ratio: 2.451, 95% confidence interval: 1.599-3.756, P < 0.001).
CONCLUSION A survival risk score model and independent prognostic variables for esophageal cancer have been developed using APOOL, EP300, PLA2G6, and VAMP7. OS for esophageal cancer might be predicted using the nomogram based on TNM stage, pathological type, and risk score. The nomogram demonstrated strong predictive ability, as shown by the concordance index, receiver operating characteristic curve, and calibration curve.
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Affiliation(s)
- Qian-Cheng Du
- Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
| | - Xin-Yu Wang
- Department of General Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Cheng-Kai Hu
- Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
| | - Ling Zhou
- Department of General Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Zheng Fu
- Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
| | - Shun Liu
- Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
| | - Jian Wang
- Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
| | - Ying-Ying Ma
- Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
| | - Meng-Yao Liu
- Department of Thoracic Surgery, Shanghai Xuhui Central Hospital, Shanghai 200031, China
| | - Hua Yu
- Department of General Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, China
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Feng J, Meng X. Histone modification and histone modification-targeted anti-cancer drugs in breast cancer: Fundamentals and beyond. Front Pharmacol 2022; 13:946811. [PMID: 36188615 PMCID: PMC9522521 DOI: 10.3389/fphar.2022.946811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/15/2022] [Indexed: 12/21/2022] Open
Abstract
Dysregulated epigenetic enzymes and resultant abnormal epigenetic modifications (EMs) have been suggested to be closely related to tumor occurrence and progression. Histone modifications (HMs) can assist in maintaining genome stability, DNA repair, transcription, and chromatin modulation within breast cancer (BC) cells. In addition, HMs are reversible, dynamic processes involving the associations of different enzymes with molecular compounds. Abnormal HMs (e.g. histone methylation and histone acetylation) have been identified to be tightly related to BC occurrence and development, even though their underlying mechanisms remain largely unclear. EMs are reversible, and as a result, epigenetic enzymes have aroused wide attention as anti-tumor therapeutic targets. At present, treatments to restore aberrant EMs within BC cells have entered preclinical or clinical trials. In addition, no existing studies have comprehensively analyzed aberrant HMs within BC cells; in addition, HM-targeting BC treatments remain to be further investigated. Histone and non-histone protein methylation is becoming an attractive anti-tumor epigenetic therapeutic target; such methylation-related enzyme inhibitors are under development at present. Consequently, the present work focuses on summarizing relevant studies on HMs related to BC and the possible mechanisms associated with abnormal HMs. Additionally, we also aim to analyze existing therapeutic agents together with those drugs approved and tested through pre-clinical and clinical trials, to assess their roles in HMs. Moreover, epi-drugs that target HMT inhibitors and HDAC inhibitors should be tested in preclinical and clinical studies for the treatment of BC. Epi-drugs that target histone methylation (HMT inhibitors) and histone acetylation (HDAC inhibitors) have now entered clinical trials or are approved by the US Food and Drug Administration (FDA). Therefore, the review covers the difficulties in applying HM-targeting treatments in clinics and proposes feasible approaches for overcoming such difficulties and promoting their use in treating BC cases.
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Basha NJ, Basavarajaiah SM. An insight into therapeutic efficacy of heterocycles as histone modifying enzyme inhibitors that targets cancer epigenetic pathways. Chem Biol Drug Des 2022; 100:682-698. [PMID: 36059065 DOI: 10.1111/cbdd.14135] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/17/2022] [Accepted: 08/21/2022] [Indexed: 01/10/2023]
Abstract
Histone modifying enzymes are the key regulators involved in the post-translational modification of histone and non-histone. These enzymes are responsible for the epigenetic control of cellular functions. However, deregulation of the activity of these enzymes results in uncontrolled disorders such as cancer and inflammatory and neurological diseases. The study includes histone acetyltransferases, deacetylases, methyl transferases, demethylases, DNA methyl transferases, and their potent inhibitors which are in a clinical trial and used as medicinal drugs. The present review covers the heterocycles as target-specific inhibitors of histone-modifying enzyme, more specifically histone acetyltransferases. This review also confers more recent reports on heterocycles as potential HAT inhibitors covered from 2016-2022 and future perspectives of these heterocycles in epigenetic therapy.
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Affiliation(s)
- N Jeelan Basha
- Department of Chemistry, Indian Academy Degree College-Autonomous, Bengaluru, Karnataka, India
| | - S M Basavarajaiah
- P.G. Department of Chemistry, Vijaya College, Bengaluru, Karnataka, India
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25
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Sarvari P, Sarvari P, Ramírez-Díaz I, Mahjoubi F, Rubio K. Advances of Epigenetic Biomarkers and Epigenome Editing for Early Diagnosis in Breast Cancer. Int J Mol Sci 2022; 23:ijms23179521. [PMID: 36076918 PMCID: PMC9455804 DOI: 10.3390/ijms23179521] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Epigenetic modifications are known to regulate cell phenotype during cancer progression, including breast cancer. Unlike genetic alterations, changes in the epigenome are reversible, thus potentially reversed by epi-drugs. Breast cancer, the most common cause of cancer death worldwide in women, encompasses multiple histopathological and molecular subtypes. Several lines of evidence demonstrated distortion of the epigenetic landscape in breast cancer. Interestingly, mammary cells isolated from breast cancer patients and cultured ex vivo maintained the tumorigenic phenotype and exhibited aberrant epigenetic modifications. Recent studies indicated that the therapeutic efficiency for breast cancer regimens has increased over time, resulting in reduced mortality. Future medical treatment for breast cancer patients, however, will likely depend upon a better understanding of epigenetic modifications. The present review aims to outline different epigenetic mechanisms including DNA methylation, histone modifications, and ncRNAs with their impact on breast cancer, as well as to discuss studies highlighting the central role of epigenetic mechanisms in breast cancer pathogenesis. We propose new research areas that may facilitate locus-specific epigenome editing as breast cancer therapeutics.
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Affiliation(s)
- Pourya Sarvari
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran P.O. Box 14965/161, Iran
| | - Pouya Sarvari
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Puebla 72160, Mexico
| | - Ivonne Ramírez-Díaz
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Puebla 72160, Mexico
- Facultad de Biotecnología, Campus Puebla, Universidad Popular Autónoma del Estado de Puebla (UPAEP), Puebla 72410, Mexico
| | - Frouzandeh Mahjoubi
- Department of Clinical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran P.O. Box 14965/161, Iran
| | - Karla Rubio
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Puebla 72160, Mexico
- Licenciatura en Médico Cirujano, Universidad de la Salud del Estado de Puebla (USEP), Puebla 72000, Mexico
- Correspondence:
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Alsamri H, Alneyadi A, Muhammad K, Ayoub MA, Eid A, Iratni R. Carnosol Induces p38-Mediated ER Stress Response and Autophagy in Human Breast Cancer Cells. Front Oncol 2022; 12:911615. [PMID: 35712465 PMCID: PMC9194514 DOI: 10.3389/fonc.2022.911615] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/03/2022] [Indexed: 11/25/2022] Open
Abstract
We recently reported that carnosol induces ROS-dependent autophagy and apoptosis in breast cancer cells. We also reported that carnosol inhibits breast cancer cell migration, invasion, and in ovo tumor growth, as well as targets STAT3, PCAF, and p300 to proteasome degradation. Here, we investigated the molecular mechanisms underlying its anti-malignant activity in breast cancer. We report that carnosol induces a ROS-dependent type I and type II programmed cell death (PCD-I or PCD-II, respectively), which occurred independently of each other. Indeed, chemical inhibition of autophagy had no effect on the induction of apoptosis, evident by the absence of cleaved PARP. Electron microscopy revealed that carnosol-treated cells exhibited enlarged endoplasmic reticulum, characteristic of ER stress. Markers of the three unfolded protein response pathways (PERK, IRE-1 α, and ATF6), namely ATF4, CHOP, phospho-IRE-1α, XBP1S, and cleaved ATF6 were upregulated in a ROS-dependent manner. In addition, carnosol induced a ROS-dependent activation of p38MAPK, increased the overall level of protein polyubiquitination, and targeted mTOR protein to proteasome degradation. Interestingly, inhibition of p38MAPK, by SB202190 and 203580, reduced cell death, selectively blocked the induction of IRE-1α and ATF6 UPR sensors and inhibited autophagy. In addition, inhibition of p38 reduced the carnosol-induced polyubiquitination and rescued mTOR, PCAF, and STAT3 from proteasomal degradation. Importantly, activation of PERK sensors and induction of apoptosis occurred independently of p38 activation. Taken together, our results suggest that ROS-dependent induced-ER stress contributes to carnosol-induced apoptotic and autophagic cell death in breast cancer cells, and further confirm that carnosol is a promising agent for breast cancer therapy.
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Affiliation(s)
- Halima Alsamri
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Aysha Alneyadi
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Khalid Muhammad
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohammed Akli Ayoub
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ali Eid
- Department of Basic Medical Sciences, College of Medicine, Qatar University Health, Qatar University, Doha, Qatar
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
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