**Duc-Hiep Bach, Seong-Hwan Kim, Ji-Young Hong, Hyen Joo Park, Dong-Chan Oh and Sang Kook Lee \***

College of Pharmacy, Seoul National University, Seoul 151-742, Korea; bdhiep90@snu.ac.kr (D.-H.B.); yanberk@snu.ac.kr (S.-H.K.); jyhong7876@daum.net (J.-Y.H.); phj00@snu.ac.kr (H.J.P.); dongchanoh@snu.ac.kr (D.-C.O.)

**\*** Author to whom correspondence should be addressed; sklee61@snu.ac.kr (S.K.L.); Tel.: +82-2-880-2475; Fax: +82-2-762-8322.

Academic Editor: Sylvia Urban

Received: 28 August 2015; Accepted: 12 November 2015; Published: 19 November 2015

**Abstract:** 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.

**Keywords:** salternamide A (SA); HIF-1α; PI3K/Akt/mTOR; p42/p44 MAPK; STAT3; cell death
