Bach Duc-Hiep, Kim Seong-Hwan, Hong Ji-Young, Park Hyen Joo, Oh Dong-Chan, Lee Sang Kook
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Mar Drugs. 2015 Nov 19;13(11):6962-76. doi: 10.3390/md13116962.
Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.
缺氧诱导因子-1α（HIF-1α）是细胞对低氧浓度反应的关键调节因子，可激活一系列基因，以对缺氧产生适应性反应。HIF-1α在多种癌症中过表达，因此是一个重要的化疗靶点。盐霉素A（SA）是一种从嗜盐链霉菌中分离出的新型小分子，是一种对多种人类癌细胞系有效的细胞毒性剂。然而，SA抑制肿瘤生长的机制仍有待阐明。在本研究中，我们证明SA在各种人类癌细胞中以时间和浓度依赖性方式有效抑制缺氧诱导的HIF-1α积累。此外，SA在缺氧条件下抑制HIF-1α的上游信号传导，如PI3K/Akt/mTOR、p42/p44 MAPK和STAT3信号传导。此外，我们发现SA通过刺激人结肠癌细胞中的G2/M细胞周期停滞和凋亡来诱导细胞死亡。综上所述，SA被鉴定为一种来自海洋天然产物的新型小分子HIF-1α抑制剂，有可能成为抗癌药物开发的主要候选药物。
