Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Non-Benzoquinone Geldanamycin Analog, WK-88-1, Induces Apoptosis in Human Breast Cancer Cell Lines

  • Zhao, Yu-Ru (School of Pharmacy, Bengbu Medical College) ;
  • Li, Hong-Mei (School of Pharmacy, Bengbu Medical College) ;
  • Zhu, Meilin (School of Pharmacy, Bengbu Medical College) ;
  • Li, Jing (School of Pharmacy, Bengbu Medical College) ;
  • Ma, Tao (School of Pharmacy, Bengbu Medical College) ;
  • Huo, Qiang (School of Pharmacy, Bengbu Medical College) ;
  • Hong, Young-Soo (Chemical Biology Research Center, KRIBB) ;
  • Wu, Cheng-Zhu (School of Pharmacy, Bengbu Medical College)
  • Received : 2017.11.06
  • Accepted : 2018.02.13
  • Published : 2018.04.28
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Abstract

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 $G_2/M$ 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 $ER-{\alpha}$ 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.

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