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      HSP90AB1 as the Druggable Target of Maggot Extract Reverses Cisplatin Resistance in Ovarian Cancer


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          Cisplatin resistance is a crucial factor affecting ovarian cancer patient's survival rate, but the primary mechanism underlying cisplatin resistance in ovarian cancer remains unclear, and this prevents the optimal use of cisplatin therapy. Maggot extract (ME) is used in traditional Chinese medicine for patients with comas and patients with gastric cancer when combined with other drug treatments. In this study, we investigated whether ME enhances the sensitivity of ovarian cancer cells to cisplatin. Two ovarian cancer cells—A2780/CDDP and SKOV3/CDDP—were treated with cisplatin and ME in vitro. SKOV3/CDDP cells that stably expressed luciferase were subcutaneously or intraperitoneally injected into BALB/c nude mice to establish a xenograft model, and this was followed by ME/cisplatin treatment. In the presence of cisplatin, ME treatment effectively suppressed the growth and metastasis of cisplatin-resistant ovarian cancer in vivo and in vitro. RNA-sequencing data showed that HSP90AB1 and IGF1R were markedly increased in A2780/CDDP cells. ME treatment markedly decreased the expression of HSP90AB1 and IGF1R, thereby increasing the expression of the proapoptotic proteins p-p53, BAX, and p-H2AX, while the opposite effects were observed for the antiapoptotic protein BCL2. Inhibition of HSP90 ATPase was more beneficial against ovarian cancer in the presence of ME treatment. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in promoting the increased expression of apoptotic proteins and DNA damage response proteins in SKOV3/CDDP cells. Inhibition of cisplatin-induced apoptosis and DNA damage by HSP90AB1 overexpression confers chemoresistance in ovarian cancer. ME can enhance the sensitivity of ovarian cancer cells to cisplatin toxicity by inhibiting HSP90AB1/IGF1R interactions, and this might represent a novel target for overcoming cisplatin resistance in ovarian cancer chemotherapy.

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          Molecular mechanisms of cisplatin resistance.

          Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNA-cisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.
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            Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches.

            Multi-drug resistance (MDR) has become the largest obstacle to the success of cancer chemotherapies. The mechanisms of MDR and the approaches to test MDR have been discovered, yet not fully understood. This review covers the in vivo and in vitro approaches for the detection of MDR in the laboratory and the mechanisms of MDR in cancers. This study also envisages the future developments toward the clinical and therapeutic applications of MDR in cancer treatment. Future therapeutics for cancer treatment will likely combine the existing therapies with drugs originated from MDR mechanisms such as anti-cancer stem cell drugs, anti-miRNA drugs or anti-epigenetic drugs. The challenges for the clinical detection of MDR will be to find new biomarkers and to determine new evaluation systems before the drug resistance emerges. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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              Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

              Abstract Traditional Chinese medicine (TCM) has been practiced for thousands of years and at the present time is widely accepted as an alternative treatment for cancer. In this review, we sought to summarize the molecular and cellular mechanisms underlying the chemopreventive and therapeutic activity of TCM, especially that of the Chinese herbal medicine‐derived phytochemicals curcumin, resveratrol, and berberine. Numerous genes have been reported to be involved when using TCM treatments and so we have selectively highlighted the role of a number of oncogene and tumor suppressor genes in TCM therapy. In addition, the impact of TCM treatment on DNA methylation, histone modification, and the regulation of noncoding RNAs is discussed. Furthermore, we have highlighted studies of TCM therapy that modulate the tumor microenvironment and eliminate cancer stem cells. The information compiled in this review will serve as a solid foundation to formulate hypotheses for future studies on TCM‐based cancer therapy.

                Author and article information

                Oxid Med Cell Longev
                Oxid Med Cell Longev
                Oxidative Medicine and Cellular Longevity
                2 May 2023
                : 2023
                : 9335440
                1The Affiliated Nanjing Drum Tower Hospital; State Key Laboratory of Analytical Chemistry for Life Science; and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China
                2Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, China
                3Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China
                4School of Medicine, Jiaxing University, Jiaxing 314001, China
                5Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
                6Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
                Author notes

                Academic Editor: Fabio Altieri

                Author information
                Copyright © 2023 Daojuan Wang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 17 October 2022
                : 22 March 2023
                : 30 March 2023
                Funded by: Key Program of Nanjing Commission of Health Department
                Award ID: ZKX20023
                Funded by: Jiangsu Commission of Health
                Award ID: H2019070
                Funded by: Jiangsu Funding Program for Excellent Postdoctoral Talent
                Award ID: 2022ZB684
                Funded by: Postdoctoral Research Foundation of China
                Award ID: 2021 M701676
                Funded by: National Natural Science Foundation of China
                Award ID: 82003077
                Award ID: 81971346
                Research Article

                Molecular medicine
                Molecular medicine


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