Non-Benzoquinone Geldanamycin Analog, WK-88-1, Induces Apoptosis in Human Breast Cancer Cell Lines

Heat shock protein 90 (HSP90) is treated as a molecular therapeutic target for the prevention and treatment of Cancer. Geldanamycin (GA) was the first identified natural HSP90 Inhibitor, but hepatotoxicity has limited its clinical application. Nevertheless, a new GA analog (WK-88- 1) with the non-benzoquinone skeleton, obtained from genetically engineered Streptomyces hygroscopicus, was found to have Anticancer activity against two human breast Cancer cell lines. WK-88-1 produced concentration-dependent inhibition of cell proliferation, cell cycle arrest, and Apoptosis in Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cell lines. Detailed analysis showed that WK-88-1 downregulated some key cell cycle molecules (CDK1 and cyclin B1) and lead to G₂/M cell cycle arrest. Further studies also showed that WK-88-1 could induce human breast Cancer cell Apoptosis by downregulating HSP90 client proteins (Akt, p-Akt, IKK, C-Raf, and Bcl-2), decreasing the ATP level, increasing Reactive Oxygen Species production, and lowering the mitochondrial membrane potential. Meanwhile, we discovered that WK-88-1 significantly decreased the levels of Her-2 and ER-α in MCF-7 cells but not in MDA-MB-231 cells. In addition, WK-88-1 significantly increased Caspase-3, -8, and -9 activities and the cleavage of PARP in a concentration-dependent manner (with the exception of Caspase-3 and PARP in MCF-7 cells). Taken together, our preliminary results suggest that WK-88-1 has the potential to play a role in breast Cancer therapy.