Frontiers in Pharmacology (Mar 2018)

A Novel Dual HDAC6 and Tubulin Inhibitor, MPT0B451, Displays Anti-tumor Ability in Human Cancer Cells in Vitro and in Vivo

  • Yi-Wen Wu,
  • Kai-Cheng Hsu,
  • Hsueh-Yun Lee,
  • Tsui-Chin Huang,
  • Tony E. Lin,
  • Yi-Ling Chen,
  • Ting-Yi Sung,
  • Jing-Ping Liou,
  • Jing-Ping Liou,
  • Wendy W. Hwang-Verslues,
  • Wendy W. Hwang-Verslues,
  • Shiow-Lin Pan,
  • Shiow-Lin Pan,
  • Wei-Chun HuangFu,
  • Wei-Chun HuangFu

DOI
https://doi.org/10.3389/fphar.2018.00205
Journal volume & issue
Vol. 9

Abstract

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The combination cancer therapy is a new strategy to circumvent drug resistance for the treatment of high metastasis and advanced malignancies. Herein, we developed a synthesized compound MPT0B451 that display inhibitory effect against histone deacetylase (HDAC) 6 and tubulin assembly. Our data demonstrated that MPT0B451 significantly inhibited cancer cell growths in HL-60 and PC-3 cells due to inhibition of HDAC activity. MPT0B451 also markedly increased caspase-mediated apoptosis in these cells. The cell cycle analysis showed mitotic arrest induced by MPT0B451 with enhanced expression of G2/M transition proteins. Moreover, molecular docking analysis supported MPT0B451 as a dual HDAC6 and tubulin inhibitor. Finally, MPT0B451 led to tumor growth inhibition (TGI) in HL-60 and PC-3 xenograft models. These findings indicated that MPT0B451 has dual inhibition effects for HDAC6 and tubulin, and also contributed to G2/M arrest followed by apoptotic induction. Together, our results suggested that MPT0B451 may serve as a potent anti-cancer treatment regimen in human prostate cancer and acute myeloid leukemia.

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