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Sharma R, Mishra A, Bhardwaj M, Singh G, Indira Harahap LV, Vanjani S, Pan CH, Nepali K. Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics. J Enzyme Inhib Med Chem 2025; 40:2489720. [PMID: 40256842 PMCID: PMC12013171 DOI: 10.1080/14756366.2025.2489720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 04/22/2025] Open
Abstract
This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related Kinase (ATR), and DNA-dependent protein kinase (DNA-PK) in the DNA damage response (DDR) and their implications in cancer. Emphasis is placed on the intricate interplay between these kinases, highlighting their collaborative and distinct roles in maintaining genomic integrity and promoting tumour development under dysregulated conditions. Furthermore, the review covers ongoing clinical trials, patent literature, and medicinal chemistry campaigns on ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, the medicinal chemistry campaigns employed robust drug design strategies and aimed at assembling new structural templates with amplified DDR kinase inhibitory ability, as well as outwitting the pharmacokinetic liabilities of the existing DDR kinase inhibitors. Given the success attained through such endeavours, the clinical pipeline of DNA repair kinase inhibitors is anticipated to be supplemented by a reasonable number of tractable entries (DDR kinase inhibitors) soon.
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Affiliation(s)
- Ram Sharma
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Anshul Mishra
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Monika Bhardwaj
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Gurpreet Singh
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | | | - Sakshi Vanjani
- Molecular Medicine, University of South Florida, Tampa, FL, USA
| | - Chun Hsu Pan
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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Fang Y, Lv X, Li G, Wang P, Zhang L, Wang R, Jia L, Liang S. Schisandrin B targets CDK4/6 to suppress proliferation and enhance radiosensitivity in nasopharyngeal carcinoma by inducing cell cycle arrest. Sci Rep 2025; 15:8452. [PMID: 40069371 PMCID: PMC11897163 DOI: 10.1038/s41598-025-92992-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 03/04/2025] [Indexed: 03/15/2025] Open
Abstract
Nasopharyngeal carcinoma (NPC) is notably prevalent in East and Southeast Asia, where despite advancements in radiotherapy leading to high control rates, challenges like radioresistance and collateral tissue damage remain significant. While Schisandrin B (SchB) has been demonstrated antitumor effects in various tumors, its efficacy in NPC remains unexplored. In this study, we explored the antitumor potential of Sch B on NPC, particularly its effects on cell proliferation and radiosensitivity. Our research demonstrates that Sch B effectively inhibits the proliferation of NPC cell lines HONE-1 and CNE-1 by inducing cell cycle G1 phase arrest, specifically through the down-regulation of cyclin-dependent kinase 4/6, without impacting the normal nasopharyngeal epithelial cell line NP69. This selective inhibitory effect positions Sch B as a targeted therapeutic agent, sparing healthy tissue from adverse effects. Furthermore, we observed that Sch B enhances the efficacy of radiotherapy in NPC cells by obstructing DNA double-strand break repair mechanisms, suggesting that a combined treatment regimen of Sch B and radiation could offer a superior therapeutic strategy. These findings propose Sch B not only as a potent inhibitor of NPC cell proliferation but also as an enhancer of radiosensitivity, providing a promising avenue for improving NPC treatment outcomes.
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Affiliation(s)
- Yanhua Fang
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Bioengineering, Dalian University of Technology, Dalian, 116024, China
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China
| | - Xinhui Lv
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China
| | - Ge Li
- Department of Oncology, Dalian Hospital of Traditional Chinese Medicine, No.321 Jiefang Street, Zhongshan District, Dalian, 116013, Liaoning, China
| | - Piao Wang
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China
- Department of Oncology, Central Hospital of Liwan, Guangzhou, 510170, China
| | - Lingling Zhang
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Ruoyu Wang
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China
| | - Lingyun Jia
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Bioengineering, Dalian University of Technology, Dalian, 116024, China.
| | - Shanshan Liang
- The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China.
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Alaouna M, Molefi T, Khanyile R, Chauke-Malinga N, Chatziioannou A, Luvhengo TE, Raletsena M, Penny C, Hull R, Dlamini Z. The potential of the South African plant Tulbaghia Violacea Harv for the treatment of triple negative breast cancer. Sci Rep 2025; 15:5737. [PMID: 39962120 PMCID: PMC11832780 DOI: 10.1038/s41598-025-88417-2] [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: 07/03/2024] [Accepted: 01/28/2025] [Indexed: 02/20/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is difficult to treat and has a low five-year survival rate. In South Africa, a large percentage of the population still relies on traditional plant-based medicine. To establish the utility of both methanol and water-soluble extracts from the leaves of Tulbaghia violacea, cytotoxicity assays were carried out to establish the IC50 values against a TNBC cell line. Cell cycle and apoptosis assays were carried out using the extracts. To identify the molecular compounds, present in water-soluble leaf extracts, NMR spectroscopy was performed. Compounds of interest were then used in computational docking studies with the anti-apoptotic protein COX-2. The IC50 values for the water- and methanol-soluble extracts were determined to be 400 and 820 µg/mL, respectively. The water-soluble extract induced apoptosis in the TNBC cell line to a greater extent than in the normal cell line. RNAseq indicated that there was an increase in the transcription of pro-apoptotic genes in the TNBC cell line. The crude extract also caused these cells to stall in the S phase. Of the 61 compounds identified in this extract, five demonstrated a high binding affinity for COX-2. Based on these findings, the compounds within the extract show significant potential for further investigation as candidates for the development of cancer therapeutics, particularly for TNBC.
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Affiliation(s)
- Mohammed Alaouna
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Thulo Molefi
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, 0001, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Richard Khanyile
- Department of Medical Oncology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, 0001, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Nkhensani Chauke-Malinga
- Papillon Aesthetics, Suite 302b Netcare Linksfield Hospital, 24 12th Ave, Linksfield West, Johannesburg, 2192, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Aristotelis Chatziioannou
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa
| | - Thifhelimbilu Emmanuel Luvhengo
- Department of Surgery, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Parktown, Johannesburg, 2193, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Maropeng Raletsena
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemistry, University of South Africa, Florida Campus, Johannesburg, South Africa
| | - Clement Penny
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Rodney Hull
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa.
| | - Zodwa Dlamini
- Department of Chemical pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
- SA-MRC Precision Oncology Research Unit (PORU), DSTI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria Hatfield, Pretoria, 0028, South Africa.
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Fang Y, Pan J, Wang P, Wang R, Liang S. A comprehensive review of Schisandrin B's preclinical antitumor activity and mechanistic insights from network pharmacology. Front Pharmacol 2025; 16:1528533. [PMID: 39995410 PMCID: PMC11847788 DOI: 10.3389/fphar.2025.1528533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 01/21/2025] [Indexed: 02/26/2025] Open
Abstract
As an active constituent in the extract of dried fruits of Schisandra chinensis, Schisandrin B exhibits diverse pharmacological effects, including liver protection, anti-inflammatory and anti-oxidant. Numerous studies have demonstrated that Schisandrin B exhibits significant antitumor activity against various malignant tumors in preclinical studies, which is achieved by inhibiting cell proliferation and metastasis and promoting apoptosis. As a potential antitumor agent, Schisandrin B holds broad application prospects. This review systematically elaborates on the antitumor effect of Schisandrin B and the related molecular mechanism, and preliminarily predicts its antitumor targets by network pharmacology, thereby pave the way for further research, development, and clinical application.
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Affiliation(s)
- Yanhua Fang
- The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
- Liaoning Key Laboratory of Molecular Recognition and Imaging, School of Bioengineering, Dalian University of Technology, Dalian, China
| | - Juan Pan
- The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Piao Wang
- The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
- Department of Oncology, Central Hospital of Liwan, Guangzhou, China
| | - Ruoyu Wang
- The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Shanshan Liang
- The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
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Zhang SS, Yu JH, Jiang SS, Wang L, Chen J, Long J, Gu SX, Li H. T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation. Eur J Pharm Biopharm 2024; 200:114327. [PMID: 38759900 DOI: 10.1016/j.ejpb.2024.114327] [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: 12/14/2023] [Revised: 03/30/2024] [Accepted: 05/14/2024] [Indexed: 05/19/2024]
Abstract
P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.
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Affiliation(s)
- Shuang-Shuang Zhang
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, Hubei, China; Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan 430205, China.
| | - Jia-Hui Yu
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, Hubei, China
| | - Si-Si Jiang
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, Hubei, China
| | - Lun Wang
- Huazhong Pharmaceutical Company Limited, Xiangyang 441021, China
| | - Jiong Chen
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, Hubei, China
| | - Jiao Long
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, Hubei, China
| | - Shuang-Xi Gu
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, Hubei, China; Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan 430205, China.
| | - Hui Li
- School of Chemical Engineering, Sichuan University, Chengdu 610065, China.
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Hsieh MJ, Lin CC, Lo YS, Chuang YC, Ho HY, Chen MK. Semilicoisoflavone B induces oral cancer cell apoptosis by targeting claspin and ATR-Chk1 signaling pathways. ENVIRONMENTAL TOXICOLOGY 2024; 39:2417-2428. [PMID: 38197544 DOI: 10.1002/tox.24107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 12/03/2023] [Accepted: 12/10/2023] [Indexed: 01/11/2024]
Abstract
The prevalence of oral squamous cell carcinoma (OSCC) is increasing worldwide mainly due to poor oral hygiene and unrestricted lifestyle. Advanced-stage OSCC is associated with poor prognosis and a 5-year survival rate of only 30%-50%. The present study was designed to investigate the anticancer effect and mode of action of Glycyrrhiza-derived semilicoisoflavone B (SFB) in 5-fluorourasil (5FU)-resistant human OSCC cell lines. The study findings revealed that SFB significantly reduces OSCC cell viability and colony formation ability by arresting cell cycle at the G2/M and S phases and reducing the expressions of key cell cycle regulators including cyclin A, cyclin B, CDC2, and CDK2. The compound caused a significant induction in the percentage of nuclear condensation and apoptotic cells in OSCC. Regarding pro-apoptotic mode of action, SFB was found to increase Fas-associated death domain and death receptor 5 expressions and reduce decoy receptor 2 expression, indicating involvement of extrinsic pathway. Moreover, SFB was found to increase pro-apoptotic Bim expression and reduce anti-apoptotic Bcl-2 and Bcl-xL expressions, indicating involvement of intrinsic pathway. Moreover, SFB-mediated induction in cleaved caspases 3, 8, and 9 and cleaved poly(ADP-ribose) polymerase confirmed the induction of caspase-mediated apoptotic pathways. Regarding upstream signaling pathway, SFB was found to reduce extracellular signal regulated kinase 1/2 (ERK) phosphorylation to execute its pro-apoptotic activity. The Human Apoptotic Array findings revealed that SFB suppresses claspin expression, which in turn caused reduced phosphorylation of ATR, checkpoint kinase 1 (Chk1), Wee1, and CDC25C, indicating disruption of ATR-Chk1 signaling pathway by SFB. Taken together, these findings indicate that SFB acts as a potent anticancer compound against 5FU-resistant OSCC by modulating mitogen-activated protein kinase (MAPK) and ATR-Chk1 signaling pathways.
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Affiliation(s)
- Ming-Ju Hsieh
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Chia-Chieh Lin
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yu-Sheng Lo
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ching Chuang
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Hsin-Yu Ho
- Oral Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Mu-Kuan Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
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Chen T, Xiao Z, Liu X, Wang T, Wang Y, Ye F, Su J, Yao X, Xiong L, Yang DH. Natural products for combating multidrug resistance in cancer. Pharmacol Res 2024; 202:107099. [PMID: 38342327 DOI: 10.1016/j.phrs.2024.107099] [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: 12/10/2023] [Revised: 01/22/2024] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
Cancer cells frequently develop resistance to chemotherapeutic therapies and targeted drugs, which has been a significant challenge in cancer management. With the growing advances in technologies in isolation and identification of natural products, the potential of natural products in combating cancer multidrug resistance has received substantial attention. Importantly, natural products can impact multiple targets, which can be valuable in overcoming drug resistance from different perspectives. In the current review, we will describe the well-established mechanisms underlying multidrug resistance, and introduce natural products that could target these multidrug resistant mechanisms. Specifically, we will discuss natural compounds such as curcumin, resveratrol, baicalein, chrysin and more, and their potential roles in combating multidrug resistance. This review article aims to provide a systematic summary of recent advances of natural products in combating cancer drug resistance, and will provide rationales for novel drug discovery.
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Affiliation(s)
- Ting Chen
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Zhicheng Xiao
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Xiaoyan Liu
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Tingfang Wang
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Yun Wang
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Fei Ye
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China
| | - Juan Su
- School of Pharmacy, Naval Medical University, Shanghai 200433, China.
| | - Xuan Yao
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
| | - Liyan Xiong
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
| | - Dong-Hua Yang
- New York College of Traditional Chinese Medicine, NY 11501, USA.
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Cardona-Mendoza A, Fonseca-Benitez A, Buitrago DM, Coy-Barrera E, Perdomo SJ. Down-regulation of human papillomavirus E6 oncogene and antiproliferative effect of Schisandra chinensis and Pueraria lobata natural extracts on Hela cell line. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117225. [PMID: 37797877 DOI: 10.1016/j.jep.2023.117225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 10/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cervical cancer is one of the most common malignancies in women that continues to be a public health problem worldwide. Human papillomavirus (HPV) infection is closely related as the causative agent of almost all cases of cervical cancer. Currently, there is no effective treatment for the persistence of HPV. Although vaccines have shown promising results in recent years, they are still a costly strategy for developing countries and have no therapeutic effect on existing infections, which is why the need arises to search for new strategies that can be used in treatment, suppressing oncogenic HPV and disease progression. Extracts of Schisandra Chinensis and Pueraria lobata have been used in traditional medicine, and it has been shown in recent years that some of their bioactive compounds have pharmacological, antioxidant, antitumor, apoptotic, and proliferation effects in HPV-positive cells. However, its mechanism of action has yet to be fully explored. AIM OF THE STUDY The following study aimed to determine the chemical composition, antioxidant activity, and potential antiproliferative and viral oncogene effects of natural extracts of S. chinensis and P. lobata on HPV-18 positive cervical cancer cells. MATERIALS AND METHODS The HPV-18-positive HeLa cells were treated for 24 and 48 h with the ethanolic extracts of S chinensis and P. lobata. Subsequently, cell viability was evaluated using the resazurin method, the effect on the cell cycle of the extracts (1.0, 10, and 100 μg/mL) was measured by flow cytometry, the gene of expression of the E6/E7, P53, BCL-2, and E2F-1 were determined by RT-PCR and the protein expression of p53, Ki-67, x|and Bcl-2 by immunohistochemistry. Additionally, the chemical characterization of the two extracts was carried out using LC-MS, and the total phenolics content (TPC), Total flavonoid content (TFC), and DPPH radical scavenging capacity were determined. Data were analyzed using the Mann-Whitney and Kruskal Wallis U test with GraphPad Prism 6 software. RESULTS The natural extracts of Schisandra chinensis and Pueraria lobata induced down-regulation of E6 HPV oncogene (p<0.05) and a strong up-regulation of P53 (p<0.05), E2F-1 (p<0.05), and Bcl-2 (p<0.05) gene expression. Simultaneously, the natural extracts tend to increase the p53 protein levels and arrest the cell cycle of HeLa in the G1/S phase (p<0.05). Investigated extracts were characterized by the occurrence of bioactive lignans and isoflavones in S. chinensis and P. lobata, respectively. CONCLUSION The extracts of S. chinensis and P. lobata within their chemical characterization mainly present lignan and isoflavone-type compounds, which are probably responsible for inhibiting the expression of the HPV E6 oncogene and inducing an increase in the expression of p53, Bcl -2 and E2F-1 producing cell cycle detection in S phase in HeLa cells. Therefore, these extracts are good candidates to continue studying their antiviral and antiproliferative potential in cells transformed by HPV.
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Affiliation(s)
- Andrés Cardona-Mendoza
- Cellular and Molecular Immunology Group-INMUBO, School of Dentistry, Universidad El Bosque, Bogotá, Colombia
| | - Angela Fonseca-Benitez
- Cellular and Molecular Immunology Group-INMUBO, School of Dentistry, Universidad El Bosque, Bogotá, Colombia
| | - Diana Marcela Buitrago
- Cellular and Molecular Immunology Group-INMUBO, School of Dentistry, Universidad El Bosque, Bogotá, Colombia; Unidad de Investigación Básica Oral-UIBO, Facultad de Odontología, Universidad El Bosque, Bogotá, Colombia
| | - Ericsson Coy-Barrera
- Bioorganic Chemistry Laboratory, Department of Chemistry, Universidad Militar Nueva Granada, Cajicá, 250247, Colombia
| | - Sandra J Perdomo
- Cellular and Molecular Immunology Group-INMUBO, School of Dentistry, Universidad El Bosque, Bogotá, Colombia.
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Biswas H, Makinwa Y, Zou Y. Novel Cellular Functions of ATR for Therapeutic Targeting: Embryogenesis to Tumorigenesis. Int J Mol Sci 2023; 24:11684. [PMID: 37511442 PMCID: PMC10380702 DOI: 10.3390/ijms241411684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/14/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
The DNA damage response (DDR) is recognized as having an important role in cancer growth and treatment. ATR (ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has shown significant therapeutic potential in cancer treatment. ATR inhibitors have shown anti-tumor effectiveness, not just as monotherapies but also in enhancing the effects of standard chemotherapy, radiation, and immunotherapy. The biological basis of ATR is examined in this review, as well as its functional significance in the development and therapy of cancer, and the justification for inhibiting this target as a therapeutic approach, including an assessment of the progress and status of previous decades' development of effective and selective ATR inhibitors. The current applications of these inhibitors in preclinical and clinical investigations as single medicines or in combination with chemotherapy, radiation, and immunotherapy are also fully reviewed. This review concludes with some insights into the many concerns highlighted or identified with ATR inhibitors in both the preclinical and clinical contexts, as well as potential remedies proposed.
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Affiliation(s)
| | | | - Yue Zou
- Department of Cell and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (H.B.); (Y.M.)
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Chevarin M, Alcantara D, Albuisson J, Collonge-Rame MA, Populaire C, Selmani Z, Baurand A, Sawka C, Bertolone G, Callier P, Duffourd Y, Jonveaux P, Bignon YJ, Coupier I, Cornelis F, Cordier C, Mozelle-Nivoix M, Rivière JB, Kuentz P, Thauvin C, Boidot R, Ghiringhelli F, O'Driscoll M, Faivre L, Nambot S. The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles. Oncotarget 2023; 14:111-125. [PMID: 36749285 PMCID: PMC9904323 DOI: 10.18632/oncotarget.28358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 01/23/2023] [Indexed: 02/08/2023] Open
Abstract
In oncogenetics, some patients could be considered as "extreme phenotypes", such as those with very early onset presentation or multiple primary malignancies, unusually high numbers of cancers of the same spectrum or rare cancer types in the same parental branch. For these cases, a genetic predisposition is very likely, but classical candidate gene panel analyses often and frustratingly remains negative. In the framework of the EX2TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of ATR (p.Leu1808*). ATR has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional ATR variants in a cohort of both male and female with early onset and familial breast cancers (c.7762-2A>C; c.2078+1G>A; c.1A>G). Further molecular and cellular investigations showed impacts on transcripts for variants affecting splicing sites and reduction of ATR expression and phosphorylation of the ATR substrate CHEK1. This work further demonstrates the interest of an extended genetic analysis such as exome sequencing to identify very rare variants that can play a role in cancer predisposition in extreme phenotype cancer cases unexplained by classical cancer gene panels testing.
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Affiliation(s)
- Martin Chevarin
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Unité Fonctionnelle Innovation diagnostique dans les maladies rares, laboratoire de génétique chromosomique et moléculaire, Plateau Technique de Biologie, CHU Dijon Bourgogne, Dijon, France
| | - Diana Alcantara
- Human DNA Damage Response Disorders Group, University of Sussex, Genome Damage and Stability Centre, Brighton, United Kingdom
| | - Juliette Albuisson
- Service d’Oncogénétique, Centre Georges François Leclerc, Dijon, France
- Département de biologie et pathologie des tumeurs, Centre Georges François Leclerc, Dijon, France
| | | | - Céline Populaire
- Oncobiologie Génétique Bioinformatique, PCBio, CHU Besançon, Besançon, France
| | - Zohair Selmani
- Oncobiologie Génétique Bioinformatique, PCBio, CHU Besançon, Besançon, France
| | - Amandine Baurand
- Service d’Oncogénétique, Centre Georges François Leclerc, Dijon, France
- Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
| | - Caroline Sawka
- Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
| | - Geoffrey Bertolone
- Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
| | - Patrick Callier
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Unité Fonctionnelle Innovation diagnostique dans les maladies rares, laboratoire de génétique chromosomique et moléculaire, Plateau Technique de Biologie, CHU Dijon Bourgogne, Dijon, France
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France
| | - Yannis Duffourd
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France
| | - Philippe Jonveaux
- Laboratoire de Génétique Médicale, INSERM U954, Hôpitaux de Brabois, Vandoeuvre les Nancy, France
| | - Yves-Jean Bignon
- Laboratoire d’Oncologie Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France
| | | | - François Cornelis
- Université Bordeaux, IMB, UMR 5251, Talence, France
- Service d’imagerie diagnostique et interventionnelle de l’adulte, Hôpital Pellegrin, CHU de Bordeaux, France
| | | | | | - Jean-Baptiste Rivière
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France
| | - Paul Kuentz
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Oncobiologie Génétique Bioinformatique, PCBio, CHU Besançon, Besançon, France
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France
| | - Christel Thauvin
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
| | - Romain Boidot
- Département de biologie et pathologie des tumeurs, Centre Georges François Leclerc, Dijon, France
| | - François Ghiringhelli
- Département d’oncologie médicale, INSERM LNC U1231, Centre Georges François Leclerc, Dijon, France
| | - Marc O'Driscoll
- Human DNA Damage Response Disorders Group, University of Sussex, Genome Damage and Stability Centre, Brighton, United Kingdom
| | - Laurence Faivre
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Service d’Oncogénétique, Centre Georges François Leclerc, Dijon, France
- Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France
| | - Sophie Nambot
- Inserm UMR 1231 GAD Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
- Service d’Oncogénétique, Centre Georges François Leclerc, Dijon, France
- Centre de Génétique et Centre de Référence Maladies Rares Anomalies du Développement de l’Interrégion Est, Hôpital d’Enfants, CHU Dijon Bourgogne, Dijon, France
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (FHU TRANSLAD), CHU Dijon Bourgogne et Université de Bourgogne-Franche Comté, Dijon, France
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11
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Salguero C, Valladolid C, Robinson HMR, Smith GCM, Yap TA. Targeting ATR in Cancer Medicine. Cancer Treat Res 2023; 186:239-283. [PMID: 37978140 DOI: 10.1007/978-3-031-30065-3_14] [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] [Indexed: 11/19/2023]
Abstract
As a key component of the DNA Damage Response, the Ataxia telangiectasia and Rad3-related (ATR) protein is a promising druggable target that is currently widely evaluated in phase I-II-III clinical trials as monotherapy and in combinations with other rational antitumor agents, including immunotherapy, DNA repair inhibitors, chemo- and radiotherapy. Ongoing clinical studies for this drug class must address the optimization of the therapeutic window to limit overlapping toxicities and refine the target population that will most likely benefit from ATR inhibition. With advances in the development of personalized treatment strategies for patients with advanced solid tumors, many ongoing ATR inhibitor trials have been recruiting patients based on their germline and somatic molecular alterations, rather than relying solely on specific tumor subtypes. Although a spectrum of molecular alterations have already been identified as potential predictive biomarkers of response that may sensitize to ATR inhibition, these biomarkers must be analytically validated and feasible to measure robustly to allow for successful integration into the clinic. While several ATR inhibitors in development are poised to address a clinically unmet need, no ATR inhibitor has yet received FDA-approval. This chapter details the underlying rationale for targeting ATR and summarizes the current preclinical and clinical landscape of ATR inhibitors currently in evaluation, as their regulatory approval potentially lies close in sight.
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Affiliation(s)
- Carolina Salguero
- Department of Investigational Cancer Therapeutics (Phase I Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christian Valladolid
- Department of Investigational Cancer Therapeutics (Phase I Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Helen M R Robinson
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK
| | - Graeme C M Smith
- Artios Pharma, The Glenn Berge Building, Babraham Research Campus, Cambridge, UK
| | - Timothy A Yap
- Department of Investigational Cancer Therapeutics (Phase I Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- The Institute for Applied Cancer Science, and Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, TX, 77030, Houston, USA.
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12
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Li S, Wang T, Fei X, Zhang M. ATR Inhibitors in Platinum-Resistant Ovarian Cancer. Cancers (Basel) 2022; 14:cancers14235902. [PMID: 36497387 PMCID: PMC9740197 DOI: 10.3390/cancers14235902] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Platinum-resistant ovarian cancer (PROC) is one of the deadliest types of epithelial ovarian cancer, and it is associated with a poor prognosis as the median overall survival (OS) is less than 12 months. Targeted therapy is a popular emerging treatment method. Several targeted therapies, including those using bevacizumab and poly (ADP-ribose) polymerase inhibitor (PARPi), have been used to treat PROC. Ataxia telangiectasia and RAD3-Related Protein Kinase inhibitors (ATRi) have attracted attention as a promising class of targeted drugs that can regulate the cell cycle and influence homologous recombination (HR) repair. In recent years, many preclinical and clinical studies have demonstrated the efficacy of ATRis in PROC. This review focuses on the anticancer mechanism of ATRis and the progress of research on ATRis for PROC.
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Affiliation(s)
- Siyu Li
- Department of Medical Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230031, China
- Department of Oncology, Anhui Medical University, Hefei 230031, China
| | - Tao Wang
- Department of Medical Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230031, China
- Department of Oncology, Anhui Medical University, Hefei 230031, China
| | - Xichang Fei
- Department of Medical Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230031, China
- Department of Oncology, Anhui Medical University, Hefei 230031, China
| | - Mingjun Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230031, China
- Department of Oncology, Anhui Medical University, Hefei 230031, China
- Correspondence:
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13
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Ahmed S, Alam W, Aschner M, Alsharif KF, Albrakati A, Saso L, Khan H. Natural products targeting the ATR-CHK1 signaling pathway in cancer therapy. Biomed Pharmacother 2022; 155:113797. [PMID: 36271573 PMCID: PMC9590097 DOI: 10.1016/j.biopha.2022.113797] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/29/2022] [Accepted: 10/02/2022] [Indexed: 11/19/2022] Open
Abstract
Cancer is one of the most severe medical conditions in the world, causing millions of deaths each year. Chemotherapy and radiotherapy are critical for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer requires novel efficacious treatment modalities. Natural remedies offer feasible alternative options against malignancy in contrast to available synthetic medication. Selective killing of cancer cells is privileged mainstream in cancer treatment, and targeted therapy represents the new tool with the potential to pursue this aim. The discovery of innovative therapies targeting essential components of DNA damage signaling and repair pathways such as ataxia telangiectasia mutated and Rad3 related Checkpoint kinase 1 (ATR-CHK1)has offered a possibility of significant therapeutic improvement in oncology. The activation and inhibition of this pathway account for chemopreventive and chemotherapeutic activity, respectively. Targeting this pathway can also aid to overcome the resistance of conventional chemo- or radiotherapy. This review enlightens the anticancer role of natural products by ATR-CHK1 activation and inhibition. Additionally, these compounds have been shown to have chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Ideally, this review will trigger interest in natural products targeting ATR-CHK1 and their potential efficacy and safety as cancer lessening agents.
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Affiliation(s)
- Salman Ahmed
- Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Waqas Alam
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue Bronx, NY 10461, USA
| | - Khalaf F Alsharif
- Department of Clinical Laboratory, College of Applied Medical Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Ashraf Albrakati
- Department of Human Anatomy, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer"Sapienza University, Rome 00185, Italy
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan.
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14
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Przystupski D, Ussowicz M. Landscape of Cellular Bioeffects Triggered by Ultrasound-Induced Sonoporation. Int J Mol Sci 2022; 23:ijms231911222. [PMID: 36232532 PMCID: PMC9569453 DOI: 10.3390/ijms231911222] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 11/18/2022] Open
Abstract
Sonoporation is the process of transient pore formation in the cell membrane triggered by ultrasound (US). Numerous studies have provided us with firm evidence that sonoporation may assist cancer treatment through effective drug and gene delivery. However, there is a massive gap in the body of literature on the issue of understanding the complexity of biophysical and biochemical sonoporation-induced cellular effects. This study provides a detailed explanation of the US-triggered bioeffects, in particular, cell compartments and the internal environment of the cell, as well as the further consequences on cell reproduction and growth. Moreover, a detailed biophysical insight into US-provoked pore formation is presented. This study is expected to review the knowledge of cellular effects initiated by US-induced sonoporation and summarize the attempts at clinical implementation.
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15
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Chan Wah Hak CML, Rullan A, Patin EC, Pedersen M, Melcher AA, Harrington KJ. Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy. Front Oncol 2022; 12:971959. [PMID: 36106115 PMCID: PMC9465159 DOI: 10.3389/fonc.2022.971959] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Radiotherapy is one of the most effective and frequently used treatments for a wide range of cancers. In addition to its direct anti-cancer cytotoxic effects, ionising radiation can augment the anti-tumour immune response by triggering pro-inflammatory signals, DNA damage-induced immunogenic cell death and innate immune activation. Anti-tumour innate immunity can result from recruitment and stimulation of dendritic cells (DCs) which leads to tumour-specific adaptive T-cell priming and immunostimulatory cell infiltration. Conversely, radiotherapy can also induce immunosuppressive and anti-inflammatory mediators that can confer radioresistance. Targeting the DNA damage response (DDR) concomitantly with radiotherapy is an attractive strategy for overcoming radioresistance, both by enhancing the radiosensitivity of tumour relative to normal tissues, and tipping the scales in favour of an immunostimulatory tumour microenvironment. This two-pronged approach exploits genomic instability to circumvent immune evasion, targeting both hallmarks of cancer. In this review, we describe targetable DDR proteins (PARP (poly[ADP-ribose] polymerase); ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) and Wee1 (Wee1-like protein kinase) and their potential intersections with druggable immunomodulatory signalling pathways, including nucleic acid-sensing mechanisms (Toll-like receptors (TLR); cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and retinoic acid-inducible gene-I (RIG-I)-like receptors), and how these might be exploited to enhance radiation therapy. We summarise current preclinical advances, recent and ongoing clinical trials and the challenges of therapeutic combinations with existing treatments such as immune checkpoint inhibitors.
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Affiliation(s)
| | - Antonio Rullan
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Emmanuel C. Patin
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Malin Pedersen
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Alan A. Melcher
- Translational Immunotherapy Team, The Institute of Cancer Research, London, United Kingdom
| | - Kevin J. Harrington
- Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom
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16
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Ma X, Zhang H, Wang S, Deng R, Luo D, Luo M, Huang Q, Yu S, Pu C, Liu Y, Tong Y, Li R. Recent Advances in the Discovery and Development of Anti-HIV Natural Products. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:1173-1196. [PMID: 35786172 DOI: 10.1142/s0192415x22500483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection is a serious public problem threatening global health. At present, although "cocktail therapy" has achieved significant clinical effects, HIV still cannot be completely eradicated. Furthermore, long-term antiviral treatment has caused problems such as toxic side effects, the emergence of drug-resistant viruses, and poor patient compliance. Therefore, it is highly necessary to continue to search for high-efficient, low-toxic anti-HIV drugs with new mechanisms. Natural products have the merits of diverse scaffolds, biological activities, and low toxicity that are deemed the important sources of drug discovery. Thus, finding lead compounds from natural products followed by structure optimization has become one of the important ways of modern drug discovery. Nowadays, many natural products have been found, such as berberine, gnidimacrin, betulone, and kuwanon-L, which exert effective anti-HIV activity through immune regulation, inhibition of related functional enzymes in HIV replication, and anti-oxidation. This paper reviewed these natural products, their related chemical structure optimization, and their anti-HIV mechanisms.
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Affiliation(s)
- Xinyu Ma
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Hongjia Zhang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Shirui Wang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Rui Deng
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Dan Luo
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Meng Luo
- Translational Skin Cancer Research, German Cancer Consortium (DKTK), Dermatology, University Duisburg-Essen, Essen, Germany
| | - Qing Huang
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Su Yu
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Chunlan Pu
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Yuanyuan Liu
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
| | - Yu Tong
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, P. R. China
| | - Rui Li
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, P. R. China
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Suzuki T, Hirokawa T, Maeda A, Harata S, Watanabe K, Yanagita T, Ushigome H, Nakai N, Maeda Y, Shiga K, Ogawa R, Mitsui A, Kimura M, Matsuo Y, Takahashi H, Takiguchi S. ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage. Oncol Rep 2022; 47:78. [PMID: 35191521 PMCID: PMC8892626 DOI: 10.3892/or.2022.8289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 01/27/2022] [Indexed: 11/06/2022] Open
Abstract
The repair of DNA damage caused by chemotherapy in cancer cells occurs mainly at two cell cycle checkpoints (G1 and G2) and is a factor contributing to chemoresistance. Most colorectal cancers harbor mutations in p53, the main pathway involved in the G1 checkpoint, and thus, are particularly dependent on the G2 checkpoint for DNA repair. The present study examined the effect of AZD6738, a specific inhibitor of ataxia telangiectasia mutated and rad3-related (ATR) involved in the G2 checkpoint, combined with 5-fluorouracil (5-FU), a central chemotherapeutic agent, on colorectal cancer cells. Since 5-FU has a DNA-damaging effect, its combination with AZD6738 is likely to enhance the therapeutic effect. The effects of the AZD6738/5-FU combination were evaluated in various colorectal cancer cells (HT29, SW480, HCT116 and DLD-1 cells) by flow cytometry (HT29 cells), western blotting (HT29 cells) and water-soluble tetrazolium 1 assays (HT29, SW480, HCT116 and DLD-1 cells), as well as in an experimental animal model (HT29 cells). In vitro, the AZD6738/5-FU combination increased the number of mitotic cells according to flow cytometry, decreased the checkpoint kinase 1 phosphorylation levels and increased cleaved caspase-3 and phosphorylated form of H2A.X variant histone levels according to western blotting, and decreased the proliferation rate of four colon cancer cell lines according to cell viability experiments. In vivo, xenografted colorectal cancer cells treated with the AZD6738/5-FU combination exhibited a marked decrease in proliferation compared with the 5-FU alone group. The present results suggested that AZD6738 enhanced the effect of 5-FU in p53-mutated colorectal cancer.
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Affiliation(s)
- Takuya Suzuki
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Takahisa Hirokawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Anri Maeda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Shinnosuke Harata
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Kaori Watanabe
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Takeshi Yanagita
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Hajime Ushigome
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Nozomi Nakai
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Yuzo Maeda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Kazuyoshi Shiga
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Ryo Ogawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Akira Mitsui
- Department of Gastroenterological Surgery, Nagoya City University West Medical Center, Nagoya, Aichi 462‑8508, Japan
| | - Masahiro Kimura
- Department of Gastroenterological Surgery, Nagoya City University East Medical Center, Nagoya, Aichi 464‑8547, Japan
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Hiroki Takahashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
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Bin H, Chen P, Wu M, Wang F, Lin G, Pan S, Liu J, Mu B, Nan J, Huang Q, Li L, Yang S. Discovery of a potent and highly selective inhibitor of ataxia telangiectasia mutated and Rad3-Related (ATR) kinase: Structural activity relationship and antitumor activity both in vitro and in vivo. Eur J Med Chem 2022; 232:114187. [DOI: 10.1016/j.ejmech.2022.114187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/28/2022] [Accepted: 02/04/2022] [Indexed: 11/26/2022]
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Botrugno OA, Tonon G. Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain? Cancers (Basel) 2021; 14:cancers14010025. [PMID: 35008191 PMCID: PMC8750813 DOI: 10.3390/cancers14010025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 12/02/2022] Open
Abstract
Simple Summary Genomic instability is recognized as a driving force in most cancers as well as in the haematological cancer multiple myeloma and remains among the leading cause of drug resistance. Several evidences suggest that replicative stress exerts a fundamental role in fuelling genomic instability. Notably, cancer cells rely on a single protein, ATR, to cope with the ensuing DNA damage. In this perspective, we provide an overview depicting how replicative stress represents an Achilles heel for multiple myeloma, which could be therapeutically exploited either alone or in combinatorial regimens to preferentially ablate tumor cells. Abstract Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.
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Affiliation(s)
- Oronza A. Botrugno
- Functional Genomics of Cancer Unit, Experimental Oncology Division, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Correspondence: (O.A.B.); (G.T.); Tel.: +39-02-2643-6661 (O.A.B.); +39-02-2643-5624 (G.T.); Fax: +39-02-2643-6352 (O.A.B. & G.T.)
| | - Giovanni Tonon
- Functional Genomics of Cancer Unit, Experimental Oncology Division, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Correspondence: (O.A.B.); (G.T.); Tel.: +39-02-2643-6661 (O.A.B.); +39-02-2643-5624 (G.T.); Fax: +39-02-2643-6352 (O.A.B. & G.T.)
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Wang M, Chen S, Ao D. Targeting DNA repair pathway in cancer: Mechanisms and clinical application. MedComm (Beijing) 2021; 2:654-691. [PMID: 34977872 PMCID: PMC8706759 DOI: 10.1002/mco2.103] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 02/05/2023] Open
Abstract
Over the last decades, the growing understanding on DNA damage response (DDR) pathways has broadened the therapeutic landscape in oncology. It is becoming increasingly clear that the genomic instability of cells resulted from deficient DNA damage response contributes to the occurrence of cancer. One the other hand, these defects could also be exploited as a therapeutic opportunity, which is preferentially more deleterious in tumor cells than in normal cells. An expanding repertoire of DDR-targeting agents has rapidly expanded to inhibitors of multiple members involved in DDR pathways, including PARP, ATM, ATR, CHK1, WEE1, and DNA-PK. In this review, we sought to summarize the complex network of DNA repair machinery in cancer cells and discuss the underlying mechanism for the application of DDR inhibitors in cancer. With the past preclinical evidence and ongoing clinical trials, we also provide an overview of the history and current landscape of DDR inhibitors in cancer treatment, with special focus on the combination of DDR-targeted therapies with other cancer treatment strategies.
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Affiliation(s)
- Manni Wang
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Siyuan Chen
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Danyi Ao
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduChina
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21
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Raimundo L, Calheiros J, Saraiva L. Exploiting DNA Damage Repair in Precision Cancer Therapy: BRCA1 as a Prime Therapeutic Target. Cancers (Basel) 2021; 13:cancers13143438. [PMID: 34298653 PMCID: PMC8303227 DOI: 10.3390/cancers13143438] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/21/2021] [Accepted: 07/07/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Chemical inhibition of central DNA damage repair (DDR) proteins has become a promising approach in precision cancer therapy. In particular, BRCA1 and its DDR-associated proteins constitute important targets for developing DNA repair inhibiting drugs. This review provides relevant insights on DDR biology and pharmacology, aiming to boost the development of more effective DDR targeted therapies. Abstract Precision medicine aims to identify specific molecular alterations, such as driver mutations, allowing tailored and effective anticancer therapies. Poly(ADP)-ribose polymerase inhibitors (PARPi) are the prototypical example of targeted therapy, exploiting the inability of cancer cells to repair DNA damage. Following the concept of synthetic lethality, PARPi have gained great relevance, particularly in BRCA1 dysfunctional cancer cells. In fact, BRCA1 mutations culminate in DNA repair defects that can render cancer cells more vulnerable to therapy. However, the efficacy of these drugs has been greatly affected by the occurrence of resistance due to multi-connected DNA repair pathways that may compensate for each other. Hence, the search for additional effective agents targeting DNA damage repair (DDR) is of crucial importance. In this context, BRCA1 has assumed a central role in developing drugs aimed at inhibiting DNA repair activity. Collectively, this review provides an in-depth understanding of the biology and regulatory mechanisms of DDR pathways, highlighting the potential of DDR-associated molecules, particularly BRCA1 and its interconnected partners, in precision cancer medicine. It also affords an overview about what we have achieved and a reflection on how much remains to be done in this field, further addressing encouraging clues for the advance of DDR targeted therapy.
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Fernandes SG, Shah P, Khattar E. Recent Advances in Therapeutic Application of DNA Damage Response Inhibitors against Cancer. Anticancer Agents Med Chem 2021; 22:469-484. [PMID: 34102988 DOI: 10.2174/1871520621666210608105735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/02/2021] [Accepted: 02/22/2021] [Indexed: 11/22/2022]
Abstract
DNA integrity is continuously challenged by intrinsic cellular processes and environmental agents. To overcome this genomic damage, cells have developed multiple signaling pathways collectively named as DNA damage response (DDR) and composed of three components: (i) sensor proteins, which detect DNA damage, (ii) mediators that relay the signal downstream and recruit the repair machinery, and (iii) the repair proteins, which restore the damaged DNA. A flawed DDR and failure to repair the damage lead to the accumulation of genetic lesions and increased genomic instability, which is recognized as a hallmark of cancer. Cancer cells tend to harbor increased mutations in DDR genes and often have fewer DDR pathways than normal cells. This makes cancer cells more dependent on particular DDR pathways and thus become more susceptible to compounds inhibiting those pathways compared to normal cells, which have all the DDR pathways intact. Understanding the roles of different DDR proteins in the DNA damage response and repair pathways and identification of their structures have paved the way for the development of their inhibitors as targeted cancer therapy. In this review, we describe the major participants of various DDR pathways, their significance in carcinogenesis, and focus on the inhibitors developed against several key DDR proteins.
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Affiliation(s)
- Stina George Fernandes
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be) University, Mumbai, India
| | - Prachi Shah
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be) University, Mumbai, India
| | - Ekta Khattar
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be) University, Mumbai, India
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Abstract
In this issue of Cancer Discovery, Yap and colleagues demonstrate in a phase I trial enrolling 22 patients diagnosed with advanced solid tumors that BAY 1895344, a new potent and specific ATR inhibitor, is safe and able to induce durable responses in ATM-deficient tumors. This compelling clinical activity paves the way for innovative combination regimens that rely on exploitation of DNA damage response defects in cancer.See related article by Yap et al., p. 80.
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Affiliation(s)
- Antoine Italiano
- Early Phase Trials Unit, Institut Bergonié, Bordeaux, France. DITEP, Gustave Roussy, Villejuif, France. University of Bordeaux, Bordeaux, France.
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24
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Katoueezadeh M, Pilehvari N, Fatemi A, Hassanshahi G, Torabizadeh SA. Inhibition of DNA damage response pathway using combination of DDR pathway inhibitors and radiation in treatment of acute lymphoblastic leukemia cells. Future Oncol 2021; 17:2803-2816. [PMID: 33960207 DOI: 10.2217/fon-2020-1072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
An alarming increase in acute lymphoblastic leukemia cases among children and adults has attracted the attention of researchers to discover new therapeutic strategies with a better prognosis. In cancer cells, the DNA damage response (DDR) pathway elements have been recognized to protect tumor cells from various stresses and cause tumor progression; targeting these DDR members is an attractive strategy for treatment of cancers. The inhibition of the DDR pathway in cancer cells for the treatment of cancers has recently been introduced. Hence, effective treatment strategies are needed for this purpose. Chemotherapy in combination with radiotherapy is considered a potential therapeutic strategy for acute leukemia. This review aims to assess the synergistic effects of these inhibitors with irradiation for the treatment of leukemia.
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Affiliation(s)
- Maryam Katoueezadeh
- Department of Hematology & Medical Laboratory Science, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, 7616911333, Iran
| | - Niloofar Pilehvari
- Department of Hematology & Medical Laboratory Science, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, 7616911333, Iran
| | - Ahmad Fatemi
- Department of Hematology & Medical Laboratory Science, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, 7616911333, Iran
| | - Gholamhossein Hassanshahi
- Molecular Medicine Research Center, Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, 7718796755, Iran
| | - Seyedeh Atekeh Torabizadeh
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, 7616911319, Iran
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Li L, Kumar AK, Hu Z, Guo Z. Small Molecule Inhibitors Targeting Key Proteins in the DNA Damage Response for Cancer Therapy. Curr Med Chem 2021; 28:963-985. [PMID: 32091326 DOI: 10.2174/0929867327666200224102309] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 01/17/2020] [Accepted: 01/29/2020] [Indexed: 11/22/2022]
Abstract
DNA damage response (DDR) is a complicated interactional pathway. Defects that occur in subordinate pathways of the DDR pathway can lead to genomic instability and cancer susceptibility. Abnormal expression of some proteins in DDR, especially in the DNA repair pathway, are associated with the subsistence and resistance of cancer cells. Therefore, the development of small molecule inhibitors targeting the chief proteins in the DDR pathway is an effective strategy for cancer therapy. In this review, we summarize the development of small molecule inhibitors targeting chief proteins in the DDR pathway, particularly focusing on their implications for cancer therapy. We present the action mode of DDR molecule inhibitors in preclinical studies and clinical cancer therapy, including monotherapy and combination therapy with chemotherapeutic drugs or checkpoint suppression therapy.
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Affiliation(s)
- Lulu Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Alagamuthu Karthick Kumar
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Zhigang Hu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
| | - Zhigang Guo
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing 210023, China
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Barnieh FM, Loadman PM, Falconer RA. Progress towards a clinically-successful ATR inhibitor for cancer therapy. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100017. [PMID: 34909652 PMCID: PMC8663972 DOI: 10.1016/j.crphar.2021.100017] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/24/2021] [Accepted: 01/24/2021] [Indexed: 02/06/2023] Open
Abstract
The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions.
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Affiliation(s)
- Francis M. Barnieh
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK
| | - Paul M. Loadman
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK
| | - Robert A. Falconer
- Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK
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Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor. Bioorg Med Chem Lett 2020; 30:127517. [PMID: 32911078 DOI: 10.1016/j.bmcl.2020.127517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 11/23/2022]
Abstract
A series of Torin2, a second-generation ATP-competitive inhibitor, analogues were biologically characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT 116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T ½ of 157 min) and internal clearance in mouse as compared to Torin2. Further, SPK 98 was also noticed to indulge in inducing premature chromatin condensation as a result of ATR/mTOR kinase inhibition at 50 nM. In a nutshell, our work presents the identification and characterization of SPK 98, a small molecule inhibitor, which exhibits improved specific inhibition for ATR at a lower concentration than Torin2.
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28
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Lapcik P, Pospisilova A, Janacova L, Grell P, Fabian P, Bouchal P. How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer? Cancers (Basel) 2020; 12:E2638. [PMID: 32947901 PMCID: PMC7563588 DOI: 10.3390/cancers12092638] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 11/17/2022] Open
Abstract
Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-κB and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (≤15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.
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Affiliation(s)
- Petr Lapcik
- Department of Biochemistry, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic; (P.L.); (A.P.); (L.J.)
| | - Anna Pospisilova
- Department of Biochemistry, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic; (P.L.); (A.P.); (L.J.)
| | - Lucia Janacova
- Department of Biochemistry, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic; (P.L.); (A.P.); (L.J.)
| | - Peter Grell
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic;
| | - Pavel Fabian
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic;
| | - Pavel Bouchal
- Department of Biochemistry, Faculty of Science, Masaryk University, 62500 Brno, Czech Republic; (P.L.); (A.P.); (L.J.)
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Harnessing DNA Replication Stress for Novel Cancer Therapy. Genes (Basel) 2020; 11:genes11090990. [PMID: 32854236 PMCID: PMC7564951 DOI: 10.3390/genes11090990] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/03/2020] [Accepted: 08/20/2020] [Indexed: 12/16/2022] Open
Abstract
DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and exogenous factors which can cause perturbations that lead to DNA damage and defective replication. This can compromise genomic stability and integrity. Genomic instability is considered as one of the hallmarks of cancer. In normal cells, various checkpoints could either activate DNA repair or induce cell death/senescence. Cancer cells on the other hand potentiate DNA replicative stress, due to defective DNA damage repair mechanism and unchecked growth signaling. Though replicative stress can lead to mutagenesis and tumorigenesis, it can be harnessed paradoxically for cancer treatment. Herein, we review the mechanism and rationale to exploit replication stress for cancer therapy. We discuss both established and new approaches targeting DNA replication stress including chemotherapy, radiation, and small molecule inhibitors targeting pathways including ATR, Chk1, PARP, WEE1, MELK, NAE, TLK etc. Finally, we review combination treatments, biomarkers, and we suggest potential novel methods to target DNA replication stress to treat cancer.
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Aleksandrov R, Hristova R, Stoynov S, Gospodinov A. The Chromatin Response to Double-Strand DNA Breaks and Their Repair. Cells 2020; 9:cells9081853. [PMID: 32784607 PMCID: PMC7464352 DOI: 10.3390/cells9081853] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 02/07/2023] Open
Abstract
Cellular DNA is constantly being damaged by numerous internal and external mutagenic factors. Probably the most severe type of insults DNA could suffer are the double-strand DNA breaks (DSBs). They sever both DNA strands and compromise genomic stability, causing deleterious chromosomal aberrations that are implicated in numerous maladies, including cancer. Not surprisingly, cells have evolved several DSB repair pathways encompassing hundreds of different DNA repair proteins to cope with this challenge. In eukaryotic cells, DSB repair is fulfilled in the immensely complex environment of the chromatin. The chromatin is not just a passive background that accommodates the multitude of DNA repair proteins, but it is a highly dynamic and active participant in the repair process. Chromatin alterations, such as changing patterns of histone modifications shaped by numerous histone-modifying enzymes and chromatin remodeling, are pivotal for proficient DSB repair. Dynamic chromatin changes ensure accessibility to the damaged region, recruit DNA repair proteins, and regulate their association and activity, contributing to DSB repair pathway choice and coordination. Given the paramount importance of DSB repair in tumorigenesis and cancer progression, DSB repair has turned into an attractive target for the development of novel anticancer therapies, some of which have already entered the clinic.
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Huang RX, Zhou PK. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther 2020; 5:60. [PMID: 32355263 PMCID: PMC7192953 DOI: 10.1038/s41392-020-0150-x] [Citation(s) in RCA: 620] [Impact Index Per Article: 124.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/20/2020] [Accepted: 03/16/2020] [Indexed: 12/19/2022] Open
Abstract
Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.
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Affiliation(s)
- Rui-Xue Huang
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, 410078, Changsha, People's Republic of China
| | - Ping-Kun Zhou
- Department of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, AMMS, 100850, Beijing, People's Republic of China.
- Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory, Guangzhou Medical University, 511436, Guangzhou, People's Republic of China.
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Yar MS, Haider K, Gohel V, Siddiqui NA, Kamal A. Synthetic lethality on drug discovery: an update on cancer therapy. Expert Opin Drug Discov 2020; 15:823-832. [PMID: 32228106 DOI: 10.1080/17460441.2020.1744560] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION A novel anticancer therapy is the need of the hour due to growing incidences of resistance to first line cancer chemotherapy. Synthetic lethality (SL) is one of the new age treatment methods being explored for combating the resistance to anticancer agents. In this method, cell mutations are exploited for the development of new therapeutic agents, where, if there is loss of function of one gene, the cell mutations can still be fixed by alternative machinery but if two genes involved in DNA repair undergo loss of function, it causes lethality to the cell. AREAS COVERED The authors condense findings of SL-based novel anticancer regimen. The review emphasizes some of the SL based clinical and preclinical studies of novel targets and therapy. EXPERT OPINION SL conceptualizes a resolution against treatment resistance to anticancer regimen by recognition of therapeutic vulnerabilities in particular cancer cells. A multitude of clinical trials associated with SL and DNA repair are being conducted that will be useful in obtaining a clearer picture pertaining to the use of cancer biomarkers and effectiveness of drugs acting via target-based molecular changes. Furthermore, new anticancer regimen focused on personalized medicines will emerge basing their development upon SL.
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Affiliation(s)
- M Shahar Yar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard , New Delhi, India
| | - Kashif Haider
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard , New Delhi, India
| | - Vivek Gohel
- Department of Pharmacology and Toxicology, NIPER SAS Nagar , Mohali, India
| | | | - Ahmed Kamal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard , New Delhi, India
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A Comprehensive Review on Schisandrin B and Its Biological Properties. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:2172740. [PMID: 32256947 PMCID: PMC7102409 DOI: 10.1155/2020/2172740] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/22/2020] [Indexed: 02/06/2023]
Abstract
Nature is a vast source of bioactive molecules and has provided an active and efficient reservoir for drug discovery. Among natural compounds, one of the most promising is Schisandrin B (Sch B), isolated from Schisandra chinensis, which was documented to possess diversified pharmacokinetic propriety, among them antioxidant, anti-inflammation, cardioprotection, and neuroprotection. Due to its large biological properties, Sch B was recorded to be a potent cure for several diseases by targeting several signaling pathways. This review is aimed at emphasizing the recent data on the biological properties of Sch B among the molecular mechanism of this drug on tumoral, cardiac, and neural diseases. The data suggest that the antitumor activities of Sch B were mainly through apoptosis and cell cycle arrest at the diver's stage. It is reported that Sch B could be used as effective chemotherapy, neuroprotection, and cardioprotection since it possesses a spectrum of biological activities; however, further investigations on the mechanism of its action and preclinical trials are still mandatory to further validate the potential of this natural drug candidate.
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Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations? Pharmacol Ther 2020; 207:107450. [DOI: 10.1016/j.pharmthera.2019.107450] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 11/22/2019] [Indexed: 12/22/2022]
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35
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Li J, Lu Y, Wang D, Quan F, Chen X, Sun R, Zhao S, Yang Z, Tao W, Ding D, Gao X, Cao Q, Zhao D, Qi R, Chen C, He L, Hu K, Chen Z, Yang Y, Luo Y. Schisandrin B prevents ulcerative colitis and colitis-associated-cancer by activating focal adhesion kinase and influence on gut microbiota in an in vivo and in vitro model. Eur J Pharmacol 2019; 854:9-21. [PMID: 30951716 DOI: 10.1016/j.ejphar.2019.03.059] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/26/2019] [Accepted: 03/28/2019] [Indexed: 12/15/2022]
Abstract
Colitis-associated cancer (CAC) has a close relationship with ulcerative colitis (UC). Therapeutic effect of Schisandrin B (SchB) on UC and CAC remains largely unknown. We investigated the preventative effect of SchB on the dextran sulphate sodium (DSS) model of UC and azoxymethane (AOM)/DSS model of CAC. Furthermore, focal adhesion kinase (FAK) activation and influence on commensal microbiota are important for UC treatment. Impact on FAK activation by SchB in UC development was evaluated in vivo and vitro. We also conducted 16S rRNA sequencing to detect regulation of gut microbiota by SchB. Enhanced protection of intestinal epithelial barrier by SchB through activating FAK contributed to protective effect on colon for the fact that protection of SchB can be reversed by inhibition of FAK phosphorylation. Furthermore, influence on gut microbiota by SchB also played a significant role in UC prevention. Our results revealed that SchB was potent to prevent UC by enhancing protection of intestinal epithelial barrier and influence on gut microbiota, which led to inhibition of CAC. SchB was potential to become a new treatment for UC and prevention of CAC.
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Affiliation(s)
- Jiani Li
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Yuan Lu
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Duowei Wang
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Fei Quan
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Chen
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Rui Sun
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Sen Zhao
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Zhisen Yang
- No.30 Middle School of Taiyuan, Taiyuan, 030002, China
| | - Weiyan Tao
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Dong Ding
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Xinghua Gao
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Qiuhua Cao
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Dandan Zhao
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Ran Qi
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Cheng Chen
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China; Jiangsu Vocational Institute of Commerce, Nanjing, 211168, China
| | - Lihua He
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Kaiyong Hu
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Zhen Chen
- Pharmacology Department, China Pharmaceutical University, Nanjing, 211198, China.
| | - Yong Yang
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
| | - Yan Luo
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
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Abstract
The chemical treatment of cancer started with the realization that DNA damaging agents such as mustard gas present notable antitumoural properties. Consequently, early drug development focused on genotoxic chemicals, some of which are still widely used in the clinic. However, the efficacy of such therapies is often limited by the side effects of these drugs on healthy cells. A refinement to this approach is to use compounds that can exploit the presence of DNA damage in cancer cells. Given that replication stress (RS) is a major source of genomic instability in cancer, targeting the RS-response kinase ataxia telangiectasia and Rad3-related protein (ATR) has emerged as a promising alternative. With ATR inhibitors now entering clinical trials, we here revisit the biology behind this strategy and discuss potential biomarkers that could be used for a better selection of patients who respond to therapy.
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Affiliation(s)
- Emilio Lecona
- Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Oscar Fernandez-Capetillo
- Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
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Prakash A, Garcia-Moreno JF, Brown JAL, Bourke E. Clinically Applicable Inhibitors Impacting Genome Stability. Molecules 2018; 23:E1166. [PMID: 29757235 PMCID: PMC6100577 DOI: 10.3390/molecules23051166] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/27/2018] [Accepted: 05/01/2018] [Indexed: 12/14/2022] Open
Abstract
Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.
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Affiliation(s)
- Anu Prakash
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 YR71 Galway, Ireland.
| | - Juan F Garcia-Moreno
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 YR71 Galway, Ireland.
| | - James A L Brown
- Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 YR71 Galway, Ireland.
| | - Emer Bourke
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 YR71 Galway, Ireland.
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38
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Bhattacharyya R, Gupta P, Bandyopadhyay SK, Patro BS, Chattopadhyay S. Coralyne, a protoberberine alkaloid, causes robust photosenstization of cancer cells through ATR-p38 MAPK-BAX and JAK2-STAT1-BAX pathways. Chem Biol Interact 2018; 285:27-39. [PMID: 29486184 DOI: 10.1016/j.cbi.2018.02.032] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/16/2018] [Accepted: 02/23/2018] [Indexed: 12/20/2022]
Abstract
Photodynamic therapy (PDT) provides an effective cancer treatment option but it requires sufficient cellular oxygen concentration to exert its photosensitizing effects. Due to hypoxic nature of most tumors, widespread clinical application of PDT is restricted and warrants development of photosensitizers which can kill cancer cells in ROS independent manner. Previously, we reported significant enhancement of the anti-cancer property of coralyne in presence of ultraviolet-A (UVA) light exposure against several human carcinoma cell lines. This study aimed at unravelling molecular cascades of events in CUVA treatment (coralyne and UVA light)-mediated photosensitization of human skin cancer. The CUVA-treatment caused robust apoptosis of A431 cancer cells, primarily through mitochondrial and lysosomal dysfunctions. Silencing of BAX conferred a significant protection against CUVA-induced apoptosis. Both lysosomal proteases and caspase-8 activation contributed to BID cleavage. Further, our results revealed that a dual signaling axis e.g., ATR-p38 MAPK and JAK2-STAT1 pathways functioned upstream of BAX activation in apoptosis response. Moreover, transient silencing of ATR and pharmacological inhibition of p38-MAPK or JAK2 significantly abolished the effect of CUVA treatment induced BAX expression and cell death, linking the extrinsic and intrinsic pathways with the observed cell death. Our data suggest that coralyne, which is known topoisomerase-I inhibitor, may be an attractive agent for photo-chemotherapeutic treatment of human skin cancers.
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Affiliation(s)
- Rahul Bhattacharyya
- Dept. of Biochemistry, KPC Medical College & Hospital, Jadavpur, 700032, Kolkata, India
| | - Pooja Gupta
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India
| | | | - Birija Sankar Patro
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India.
| | - Subrata Chattopadhyay
- Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India
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Qiu Z, Oleinick NL, Zhang J. ATR/CHK1 inhibitors and cancer therapy. Radiother Oncol 2017; 126:450-464. [PMID: 29054375 DOI: 10.1016/j.radonc.2017.09.043] [Citation(s) in RCA: 226] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 08/01/2017] [Accepted: 09/30/2017] [Indexed: 02/06/2023]
Abstract
The cell cycle checkpoint proteins ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) and its major downstream effector checkpoint kinase 1 (CHK1) prevent the entry of cells with damaged or incompletely replicated DNA into mitosis when the cells are challenged by DNA damaging agents, such as radiation therapy (RT) or chemotherapeutic drugs, that are the major modalities to treat cancer. This regulation is particularly evident in cells with a defective G1 checkpoint, a common feature of cancer cells, due to p53 mutations. In addition, ATR and/or CHK1 suppress replication stress (RS) by inhibiting excess origin firing, particularly in cells with activated oncogenes. Those functions of ATR/CHK1 make them ideal therapeutic targets. ATR/CHK1 inhibitors have been developed and are currently used either as single agents or paired with radiotherapy or a variety of genotoxic chemotherapies in preclinical and clinical studies. Here, we review the status of the development of ATR and CHK1 inhibitors. We also discuss the potential mechanisms by which ATR and CHK1 inhibition induces cell killing in the presence or absence of exogenous DNA damaging agents, such as RT and chemotherapeutic agents. Lastly, we discuss synthetic lethality interactions between the inhibition of ATR/CHK1 and defects in other DNA damage response (DDR) pathways/genes.
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Affiliation(s)
- Zhaojun Qiu
- Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, USA
| | - Nancy L Oleinick
- Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, USA
| | - Junran Zhang
- Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, USA.
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40
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Carrassa L, Damia G. DNA damage response inhibitors: Mechanisms and potential applications in cancer therapy. Cancer Treat Rev 2017; 60:139-151. [PMID: 28961555 DOI: 10.1016/j.ctrv.2017.08.013] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/26/2017] [Accepted: 08/01/2017] [Indexed: 02/06/2023]
Abstract
Over the last decade the unravelling of the molecular mechanisms of the DNA damage response pathways and of the genomic landscape of human tumors have paved the road to new therapeutic approaches in oncology. It is now clear that tumors harbour defects in different DNA damage response steps, mainly signalling and repair, rendering them more dependent on the remaining pathways. We here focus on the proteins ATM, ATR, CHK1 and WEE1, reviewing their roles in the DNA damage response and as targets in cancer therapy. In the last decade specific inhibitors of these proteins have been designed, and their potential antineoplastic activity has been explored both in monotherapy strategies against tumors with specific defects (synthetic lethality approach) and in combination with radiotherapy or chemotherapeutic or molecular targeted agents. The preclinical and clinical evidence of antitumor activity of these inhibitors emanating from these research efforts will be critically reviewed. Lastly, the potential therapeutic feasibility of combining together such inhibitors with the aim to target particular subsets of tumors will be also discussed.
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Affiliation(s)
- Laura Carrassa
- Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
| | - Giovanna Damia
- Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
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41
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Wang S, Wang A, Shao M, Lin L, Li P, Wang Y. Schisandrin B reverses doxorubicin resistance through inhibiting P-glycoprotein and promoting proteasome-mediated degradation of survivin. Sci Rep 2017; 7:8419. [PMID: 28827665 PMCID: PMC5567212 DOI: 10.1038/s41598-017-08817-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 04/03/2017] [Indexed: 01/13/2023] Open
Abstract
Acquired drug resistance poses a great challenge in cancer therapy. Drug efflux and anti-apoptotic processes are the most two common mechanisms that confer cancer drug resistance. In this study, we found that Schisandrin B (Sch B), one of the major dibenzocyclooctadiene derivatives extracted from Chinese herbal medicine Schisandrae Chinensis Fructus, could significantly enhance the sensitivity of doxorubicin (DOX)-resistant breast cancer and ovarian cancer cells to DOX. Our results showed that Sch B increased the intracellular accumulation of DOX through inhibiting expression and activity of P-glycoprotein (P-gp). Meanwhile, Sch B could markedly downregulate the expression of anti-apoptotic protein survivin. Overexpression of survivin attenuated the sensitizing effects of Sch B, while silencing of survivin enhanced Sch B-mediated sensitizing effects. Furthermore, Sch B preferentially promoted chymotryptic activity of the proteasome in a concentration-dependent manner, and the proteasome inhibitor MG-132 prevented Sch B-induced survivin downregulation. Taken together, our findings suggest that Sch B could be a potential candidate for combating drug resistant cancer via modulating two key factors that responsible for cancer resistance.
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Affiliation(s)
- Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
| | - Anqi Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
| | - Min Shao
- Department of Bioengineering, Zunyi Medical University Zhuhai Campus, Zhuhai, Guangdong, 519041, China
| | - Ligen Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
| | - Peng Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China.
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China.
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42
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Sun R, Zhai R, Ma C, Wei M. WITHDRAWN: The anti-growth and anti-metastasis effects of Schisandrin B on hepatocarcinoma cells in vitro and in vivo. Biochem Biophys Res Commun 2017:S0006-291X(17)31134-8. [PMID: 28601638 DOI: 10.1016/j.bbrc.2017.06.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 06/07/2017] [Indexed: 12/18/2022]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- Ruijie Sun
- Department of Hepatobiliary Surgery, Jining First People's Hospital, Jining, Shandong, 272000, China
| | - Ruiren Zhai
- Tumor Center Shandong Sunshine Hospital, Weifang, Shandong, 261041, China
| | - Changlin Ma
- Department of Hepatobiliary Surgery, Jining First People's Hospital, Jining, Shandong, 272000, China
| | - Miao Wei
- Department of Health Care, Jining First People's Hospital, Jining, Shandong, 272000, China
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43
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Sundar R, Brown J, Ingles Russo A, Yap TA. Targeting ATR in cancer medicine. Curr Probl Cancer 2017; 41:302-315. [PMID: 28662958 DOI: 10.1016/j.currproblcancer.2017.05.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 05/04/2017] [Accepted: 05/15/2017] [Indexed: 12/21/2022]
Abstract
DNA damage occurs continually through various intrinsic and extrinsic mechanisms such as ultraviolet radiation, smoking, reactive oxygen species, and errors during replication. The cellular DNA damage response (DDR) comprises signaling networks that regulate a spectrum of processes, including cell cycle progression, which enable DNA repair to occur. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and rad3-related (ATR) kinase are 2 key regulators of the DDR cell cycle checkpoints. ATR plays an essential role in the repair of replication-associated DNA damage, while ATM is activated by DNA double-strand breaks. The investigation of cell cycle checkpoint signaling through ATR and ATM, as well as the relevant pathways involved in oncogenesis and cancer progression, has led to the discovery and development of potent and selective ATR inhibitors (ATRi). Preclinical data have demonstrated that ATR inhibition leads to tumor synthetic lethality in specific molecular contexts, and it exhibits synergy in combination with different antitumor therapies, including chemotherapy, radiotherapy, and poly(ADP-ribose) polymerase inhibitors. ATRi are now being assessed in early-phase clinical trials as single agents and in combinatorial regimens, including platinum and other chemotherapies, radiotherapy, poly(ADP-ribose) polymerase inhibitors, and immune checkpoint inhibitors. This article details the preclinical biology leading to the discovery and development of novel ATRi and discusses the rationale for monotherapy and combination antitumor strategies. We focus on the clinical development of ATRi and discuss the progress made in identifying putative predictive biomarkers of response for patient selection, such as p53, ATM, ARID1A, and other DDR aberrations.
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Affiliation(s)
- Raghav Sundar
- Drug Development Unit, Royal Marsden Hospital, London, UK; Department of Haematology-Oncology, National University Health System, Singapore
| | - Jessica Brown
- Drug Development Unit, Royal Marsden Hospital, London, UK
| | - Alvaro Ingles Russo
- Drug Development Unit, Royal Marsden Hospital, London, UK; The Institute of Cancer Research, London, UK
| | - Timothy A Yap
- Drug Development Unit, Royal Marsden Hospital, London, UK; The Institute of Cancer Research, London, UK.
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44
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Targeting the ATR-CHK1 Axis in Cancer Therapy. Cancers (Basel) 2017; 9:cancers9050041. [PMID: 28448462 PMCID: PMC5447951 DOI: 10.3390/cancers9050041] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 04/23/2017] [Accepted: 04/25/2017] [Indexed: 12/14/2022] Open
Abstract
Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented.
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45
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Lu Y, Knapp M, Crawford K, Warne R, Elling R, Yan K, Doyle M, Pardee G, Zhang L, Ma S, Mamo M, Ornelas E, Pan Y, Bussiere D, Jansen J, Zaror I, Lai A, Barsanti P, Sim J. Rationally Designed PI3Kα Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors. J Mol Biol 2017; 429:1684-1704. [PMID: 28433539 DOI: 10.1016/j.jmb.2017.04.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 04/08/2017] [Accepted: 04/11/2017] [Indexed: 12/16/2022]
Abstract
ATR, a protein kinase in the PIKK family, plays a critical role in the cell DNA-damage response and is an attractive anticancer drug target. Several potent and selective inhibitors of ATR have been reported showing significant antitumor efficacy, with most advanced ones entering clinical trials. However, due to the absence of an experimental ATR structure, the determinants contributing to ATR inhibitors' potency and specificity are not well understood. Here we present the mutations in the ATP-binding site of PI3Kα to progressively transform the pocket to mimic that of ATR. The generated PI3Kα mutants exhibit significantly improved affinity for selective ATR inhibitors in multiple chemical classes. Furthermore, we obtained the X-ray structures of the PI3Kα mutants in complex with the ATR inhibitors. The crystal structures together with the analysis on the inhibitor affinity profile elucidate the roles of individual amino acid residues in the binding of ATR inhibitors, offering key insights for the binding mechanism and revealing the structure features important for the specificity of ATR inhibitors. The ability to obtain structural and binding data for these PI3Kα mutants, together with their ATR-like inhibitor binding profiles, makes these chimeric PI3Kα proteins valuable model systems for structure-based inhibitor design.
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Affiliation(s)
- Yipin Lu
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
| | - Mark Knapp
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
| | - Kenneth Crawford
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Robert Warne
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Robert Elling
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Kelly Yan
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Michael Doyle
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Gwynn Pardee
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Li Zhang
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Sylvia Ma
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Mulugeta Mamo
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Elizabeth Ornelas
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Yue Pan
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Dirksen Bussiere
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Johanna Jansen
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Isabel Zaror
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Albert Lai
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Paul Barsanti
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
| | - Janet Sim
- Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA
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Ghelli Luserna di Rora’ A, Iacobucci I, Martinelli G. The cell cycle checkpoint inhibitors in the treatment of leukemias. J Hematol Oncol 2017; 10:77. [PMID: 28356161 PMCID: PMC5371185 DOI: 10.1186/s13045-017-0443-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/15/2017] [Indexed: 01/25/2023] Open
Abstract
The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.
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Affiliation(s)
| | - I. Iacobucci
- Department of Hematology and Medical Sciences “L. and A. Seràgnoli”, Bologna University, Bologna, Italy
- Present: Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN USA
| | - G. Martinelli
- Department of Hematology and Medical Sciences “L. and A. Seràgnoli”, Bologna University, Bologna, Italy
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47
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Ronco C, Martin AR, Demange L, Benhida R. ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells. MEDCHEMCOMM 2016; 8:295-319. [PMID: 30108746 DOI: 10.1039/c6md00439c] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/25/2016] [Indexed: 12/15/2022]
Abstract
DNA inevitably undergoes a high number of damages throughout the cell cycle. To preserve the integrity of the genome, cells have developed a complex enzymatic machinery aimed at sensing and repairing DNA lesions, pausing the cell cycle to provide more time to repair, or induce apoptosis if damages are too severe. This so-called DNA-damage response (DDR) is yet considered as a major source of resistance to DNA-damaging treatments in oncology. Recently, it has been hypothesized that cancer stem cells (CSC), a sub-population of cancer cells particularly resistant and with tumour-initiating ability, allow tumour re-growth and cancer relapse. Therefore, DDR appears as a relevant target to sensitize cancer cells and cancer stem cells to classical radio- and chemotherapies as well as to overcome resistances. Moreover, the concept of synthetic lethality could be particularly efficiently exploited in DDR. Five kinases play pivotal roles in the DDR: ATM, ATR, CHK1, CHK2 and WEE1. Herein, we review the drugs targeting these proteins and the inhibitors used in the specific case of CSC. We also suggest molecules that may be of interest for preclinical and clinical researchers studying checkpoint inhibition to sensitize cancer and cancer stem cells to DNA-damaging treatments.
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Affiliation(s)
- Cyril Ronco
- Université Côte d'Azur , CNRS , Institut de Chimie de Nice , UMR7272 - Parc Valrose , 06108 Nice Cedex 2 , France . ; ; Tel: +33 4 92076143
| | - Anthony R Martin
- Université Côte d'Azur , CNRS , Institut de Chimie de Nice , UMR7272 - Parc Valrose , 06108 Nice Cedex 2 , France . ; ; Tel: +33 4 92076143
| | - Luc Demange
- Université Côte d'Azur , CNRS , Institut de Chimie de Nice , UMR7272 - Parc Valrose , 06108 Nice Cedex 2 , France . ; ; Tel: +33 4 92076143.,Université Paris Descartes , Sorbonne Paris Cité , UFR des Sciences Pharmaceutiques , 4 avenue de l'Observatoire , Paris Fr-75006 , France.,Université Paris Descartes , Sorbonne Paris Cité , UFR Biomédicale des Saints Pères , 45 rue des Saints Pères , France
| | - Rachid Benhida
- Université Côte d'Azur , CNRS , Institut de Chimie de Nice , UMR7272 - Parc Valrose , 06108 Nice Cedex 2 , France . ; ; Tel: +33 4 92076143
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Yang SH, Kuo TC, Wu H, Guo JC, Hsu C, Hsu CH, Tien YW, Yeh KH, Cheng AL, Kuo SH. Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer. World J Gastroenterol 2016; 22:7275-7288. [PMID: 27621574 PMCID: PMC4997635 DOI: 10.3748/wjg.v22.i32.7275] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/20/2016] [Accepted: 07/21/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to co-administration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA double-strand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer.
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Yang X, Wang S, Mu Y, Zheng Y. Schisandrin B inhibits cell proliferation and induces apoptosis in human cholangiocarcinoma cells. Oncol Rep 2016; 36:1799-806. [PMID: 27499090 PMCID: PMC5022873 DOI: 10.3892/or.2016.4992] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/01/2016] [Indexed: 01/09/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common hepatic cancer with high resistance to current chemotherapies and extremely poor prognosis. The present study aimed to examine the effects of schisandrin B (Sch B) on CCA cells both in vitro and in vivo and to examine its underlying mechanism. We found that Sch B inhibited the viability and proliferation of CCA cells in a dose- and time-dependent manner as assessed by MTT and colony formation assays. The flow cytometric assay revealed G0/G1 phase arrest in the Sch B-treated HCCC-9810 and RBE cells. In addition, Sch B induced intrahepatic cholangiocarcinoma apoptosis as shown by the results of Annexin V/PI double staining. Rhodamine 123 staining revealed that Sch B decreased the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanistically, western blot analysis indicated that Sch B induced apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved PARP, and by downregulating cyclin D1, Bcl-2 and CDK-4. Moreover, Sch B significantly inhibited HCCC-9810 xenograft growth in athymic nude mice. In summary, these findings suggest that Sch B exhibited potent antitumor activities via the induction of CCA apoptosis and that Sch B may be a promising drug for the treatment of CCA.
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Affiliation(s)
- Xiaohui Yang
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, P.R. China
| | - Shuai Wang
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, P.R. China
| | - Yunchuan Mu
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, P.R. China
| | - Yixiong Zheng
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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Drugging ATR: progress in the development of specific inhibitors for the treatment of cancer. Future Med Chem 2016; 7:873-91. [PMID: 26061106 DOI: 10.4155/fmc.15.33] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
In this article, we review the ATR inhibitor field from initial pharmacological tools to first-generation clinical candidates with the potential to bring benefit to cancer patients. ATR is a critical part of the cell DNA-damage response. Over the past decade or more, compounds with weak ATR potency and low specificity have been used as tools in early studies to elucidate ATR pharmacology. More recently highly potent, selective and in vivo active ATR inhibitors have been developed enabling detailed preclinical in vitro and in vivo target assessment to be made. The published studies reveal the potential of ATR inhibitors for use as monotherapy or in combination with DNA-damaging agents. To date, VX-970 and AZD6738, have entered clinical assessment.
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