The Centenary Institute, Newtown, New South Wales, Australia.
Clin Cancer Res. 2012 Feb 1;18(3):783-95. doi: 10.1158/1078-0432.CCR-11-1166. Epub 2011 Dec 15.
Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a small-molecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL, and BCL-w and shows promise for treating leukemia, lymphoma, and small-cell lung cancer. Melanoma cells are insensitive to ABT-737, but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound.
The efficacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by short hairpin RNA-mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a three-dimensional organotypic spheroid model, and an in vivo model.
MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 but, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in three-dimensional melanoma spheroids through reduced NOXA expression, although experiments with both xenografts and three-dimensional spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics.
Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers.
黑色素瘤的耐药性通常归因于无效的凋亡途径。抑制抗凋亡 BCL-2 及其相关蛋白是一种有吸引力的策略，可以使淋巴恶性肿瘤对药物敏感，但对于黑色素瘤和其他实体瘤，这种策略在很大程度上并不成功。ABT-737 是一种小分子 BH3 模拟物，可选择性抑制 BCL-2、BCL-XL 和 BCL-w，并有望用于治疗白血病、淋巴瘤和小细胞肺癌。黑色素瘤细胞对 ABT-737 不敏感，但据报道，MCL-1 抑制可增加其他肿瘤对该化合物的敏感性。
通过短发夹 RNA 介导的敲低或其拮抗剂 NOXA 的过表达，在二维细胞培养、三维组织球模型和体内模型中研究了 MCL-1 和 BFL-1 抑制对 ABT-737 增敏黑色素瘤细胞的作用。
MCL-1 下调或 NOXA 过表达可显著增强黑色素瘤细胞对 ABT-737 的敏感性。诱导 NOXA 的细胞毒性药物也可强烈增敏黑色素瘤对 ABT-737 的敏感性，但令人惊讶的是，反之则不然。最适合的药物不一定是通常用于治疗黑色素瘤的药物。在三维黑色素瘤球体中，由于 NOXA 表达减少，ABT-737 的耐药性迅速发生，尽管异种移植和三维球体的实验表明，ABT-737 进入肿瘤块的渗透可能是主要限制因素，这可能通过使用更具扩散性的 BH3 模拟物来避免。
通过诱导 NOXA 的细胞毒性药物使肿瘤对 BH3 模拟物敏感是一种值得探索的治疗策略，可用于治疗黑色素瘤和其他实体癌。
