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Planispine A 通过抑制范可尼贫血途径使癌细胞对顺铂敏感。

Planispine A Sensitized Cancer Cells to Cisplatin by Inhibiting the Fanconi Anemia Pathway.

机构信息

Department of Biotechnology, Manipur University, Canchipur, Imphal 795003, Manipur, India.

Institute of Bioresources and Sustainable Development, Takyelpat, Imphal 795001, Manipur, India.

出版信息

Molecules. 2022 Oct 26;27(21):7288. doi: 10.3390/molecules27217288.

DOI:10.3390/molecules27217288
PMID:36364114
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9654912/
Abstract

The use of cisplatin as a chemotherapeutic drug is impeded by the development of drug resistance. Combination therapies of a chemosensitizer for cisplatin have been studied, but with little success, and the search for an effective combination therapy is continuing. Our earlier reports have shown that DC. extract enhances the apoptotic effect of cisplatin in cancer cell lines. In this study, we purified and identified the bioactive phytocompound through bio-assay-guided purification, using column chromatography and HPLC. Chemical characterization using NMR and mass spectrometry revealed the compound as planispine A, with molecular structure CHO and molecular weight, 426.16 g/mol. Planispine A was found to inhibit cancer cell proliferation in a dose-dependent manner and to sensitize the cancer cells to cisplatin-augmented apoptotic cell death, in a caspase-dependent manner. A combination of planispine A and cisplatin induced S-phase cell cycle arrest, and reduced the expression of survival proteins such as cyclin D1. Interestingly, planispine A inhibits the Fanconi anemia pathway, as shown by reduced FANCD2 foci formation and FANCD2 monoubiquitination, which revealed the molecular mechanism of chemo-sensitization of cancer cells to cisplatin. Evaluation of this combination therapy in cisplatin-resistant tumors may lead to more efficient cisplatin treatment.

摘要

顺铂作为一种化疗药物的应用受到耐药性发展的阻碍。已经研究了顺铂的化疗增敏剂联合疗法，但收效甚微，仍在继续寻找有效的联合疗法。我们之前的报告表明，DC 提取物增强了顺铂在癌细胞系中的凋亡作用。在这项研究中，我们通过生物测定指导的纯化，使用柱层析和 HPLC 从生物活性植物提取物中进行了纯化物的分离和鉴定。使用 NMR 和质谱进行的化学表征揭示了该化合物为长春胺 A，具有 CHO 的分子结构和 426.16 g/mol 的分子量。长春胺 A 被发现以剂量依赖的方式抑制癌细胞增殖，并以 caspase 依赖的方式使癌细胞对顺铂增强的凋亡细胞死亡敏感。长春胺 A 与顺铂的联合使用诱导 S 期细胞周期停滞，并降低了生存蛋白（如 cyclin D1）的表达。有趣的是，长春胺 A 抑制了范可尼贫血途径，如 FANCD2 焦点形成和 FANCD2 单泛素化减少所示，这揭示了癌细胞对顺铂化疗增敏的分子机制。在顺铂耐药肿瘤中评估这种联合治疗可能会导致更有效的顺铂治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/db168ade2603/molecules-27-07288-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/77e0f7c2b8fb/molecules-27-07288-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/e4ad8030daca/molecules-27-07288-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/413f3d11e4a8/molecules-27-07288-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/f41217b075ae/molecules-27-07288-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/8b82462ed09d/molecules-27-07288-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/db168ade2603/molecules-27-07288-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/77e0f7c2b8fb/molecules-27-07288-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/e4ad8030daca/molecules-27-07288-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/413f3d11e4a8/molecules-27-07288-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/f41217b075ae/molecules-27-07288-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/8b82462ed09d/molecules-27-07288-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2c0f/9654912/db168ade2603/molecules-27-07288-g006.jpg

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