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c-Myc-Max异二聚化抑制剂100258-F4对卵巢癌细胞的抗肿瘤作用评估

Evaluation of the antitumor effects of c-Myc-Max heterodimerization inhibitor 100258-F4 in ovarian cancer cells.

作者信息

Wang Jiandong, Ma Xiaoli, Jones Hannah M, Chan Leo Li-Ying, Song Fang, Zhang Weiyuan, Bae-Jump Victoria L, Zhou Chunxiao

机构信息

Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

出版信息

J Transl Med. 2014 Aug 21;12:226. doi: 10.1186/s12967-014-0226-x.

DOI:10.1186/s12967-014-0226-x
PMID:25143136
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4160551/
Abstract

Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma. Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. Our objective was to evaluate the potential effects of small-molecule c-Myc inhibitor, 10058-F4, on ovarian carcinoma cells and the underlying mechanisms by which 10058-F4 exerts its actions. Using MTT assay, colony formation, flow cytometry and Annexin V FITC assays, we found that 10058-F4 significantly inhibited cell proliferation of both SKOV3 and Hey ovarian cancer cells in a dose dependent manner through induction of apoptosis and cell cycle G1 arrest. Treatment with 10058-F4 reduced cellular ATP production and ROS levels in SKOV3 and Hey cells. Consistently, primary cultures of ovarian cancer treated with 10058-F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. The response to 10058-F4 was independent the level of c-Myc protein over-expression in primary cultures of ovarian carcinoma. These novel findings suggest that the growth of ovarian cancer cells is dependent upon c-MYC activity and that targeting c-Myc-Max heterodimerization could be a potential therapeutic strategy for ovarian cancer.

摘要

上皮性卵巢癌是最致命的妇科癌症，因其发病隐匿且复发时对化疗耐药。癌基因c-Myc的过表达是卵巢癌中最常见的事件之一。破坏c-Myc及其下游靶基因的功能是一种很有前景的癌症治疗策略。我们的目的是评估小分子c-Myc抑制剂10058-F4对卵巢癌细胞的潜在影响以及10058-F4发挥作用的潜在机制。通过MTT法、集落形成实验、流式细胞术和膜联蛋白V FITC检测，我们发现10058-F4通过诱导凋亡和使细胞周期停滞在G1期，以剂量依赖的方式显著抑制SKOV3和Hey卵巢癌细胞的增殖。用10058-F4处理可降低SKOV3和Hey细胞中的细胞ATP生成量和ROS水平。同样，用10058-F4处理的卵巢癌原代培养物在18例中有15例显示出caspase-3活性的诱导和细胞增殖的抑制。在卵巢癌原代培养物中，对10058-F4的反应与c-Myc蛋白过表达水平无关。这些新发现表明，卵巢癌细胞的生长依赖于c-MYC活性，靶向c-Myc-Max异二聚化可能是卵巢癌的一种潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/1f71631fe5bb/12967_2014_226_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/ed579fec5c68/12967_2014_226_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/a178b2346123/12967_2014_226_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/2e17b831e105/12967_2014_226_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/a7f941f6d303/12967_2014_226_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/1f71631fe5bb/12967_2014_226_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/ed579fec5c68/12967_2014_226_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/a178b2346123/12967_2014_226_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/2e17b831e105/12967_2014_226_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/a7f941f6d303/12967_2014_226_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f0/4160551/1f71631fe5bb/12967_2014_226_Fig5_HTML.jpg

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