Delaney Joe R, Patel Chandni, McCabe Katelyn E, Lu Dan, Davis Mitzie-Ann, Tancioni Isabelle, von Schalscha Tami, Bartakova Alena, Haft Carley, Schlaepfer David D, Stupack Dwayne G
Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, CA, USA.
Oncotarget. 2015 Oct 13;6(31):31104-18. doi: 10.18632/oncotarget.5093.
Serous Ovarian Cancers (SOC) are frequently resistant to programmed cell death. However, here we describe that these programmed death-resistant cells are nonetheless sensitive to agents that modulate autophagy. Cytotoxicity is not dependent upon apoptosis, necroptosis, or autophagy resolution. A screen of NCBI yielded more than one dozen FDA-approved agents displaying perturbed autophagy in ovarian cancer. The effects were maximized via combinatorial use of the agents that impinged upon distinct points of autophagy regulation. Autophagosome formation correlated with efficacy in vitro and the most cytotoxic two agents gave similar effects to a pentadrug combination that impinged upon five distinct modulators of autophagy. However, in a complex in vivo SOC system, the pentadrug combination outperformed the best two, leaving trace or no disease and with no evidence of systemic toxicity. Targeting the autophagy pathway in a multi-modal fashion might therefore offer a clinical option for treating recalcitrant SOC.
浆液性卵巢癌（SOC）通常对程序性细胞死亡具有抗性。然而，我们在此描述，这些抗程序性死亡的细胞对调节自噬的药物仍然敏感。细胞毒性不依赖于凋亡、坏死性凋亡或自噬的消退。对美国国立医学图书馆（NCBI）的筛选产生了十几种FDA批准的药物，这些药物在卵巢癌中显示出自噬受到干扰。通过组合使用作用于自噬调节不同点的药物，效果得以最大化。自噬体形成与体外疗效相关，最具细胞毒性的两种药物与作用于五种不同自噬调节剂的五药组合产生了相似的效果。然而，在一个复杂的体内SOC系统中，五药组合的表现优于最佳的两种药物，使疾病残留极少或无残留，且无全身毒性的证据。因此，以多模式方式靶向自噬途径可能为治疗难治性SOC提供一种临床选择。
