HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells |
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| Authors: | Ji Yoon Kim Seung Yoon Han Jung Yoo Go Woon Kim Yu Hyun Jeon Sang Wu Lee Jongsun Park So Hee Kwon |
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| Affiliation: | 1.College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea; (J.Y.K.); (S.Y.H.); (J.Y.); (G.W.K.); (Y.H.J.); (S.W.L.);2.Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, Korea;3.Metabolic Syndrome and Cell Signaling Laboratory, Department of Medical Science, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon 35015, Korea |
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| Abstract: | HDAC6 is overexpressed in ovarian cancer and is known to be correlated with tumorigenesis. Accordingly, ACY-241, a selective HDAC6 inhibitor, is currently under clinical trial and has been tested in combination with various drugs. HDAC8, another member of the HDAC family, has recently gained attention as a novel target for cancer therapy. Here, we evaluated the synergistic anticancer effects of PCI-34051 and ACY-241 in ovarian cancer. Among various ovarian cancer cells, PCI-34051 effectively suppresses cell proliferation in wild-type p53 ovarian cancer cells compared with mutant p53 ovarian cancer cells. In ovarian cancer cells harboring wild-type p53, PCI-34051 in combination with ACY-241 synergistically represses cell proliferation, enhances apoptosis, and suppresses cell migration. The expression of pro-apoptotic proteins is synergistically upregulated, whereas the expressions of anti-apoptotic proteins and metastasis-associated proteins are significantly downregulated in combination treatment. Furthermore, the level of acetyl-p53 at K381 is synergistically upregulated upon combination treatment. Overall, co-inhibition of HDAC6 and HDAC8 through selective inhibitors synergistically suppresses cancer cell proliferation and metastasis in p53 wild-type ovarian cancer cells. These results suggest a novel approach to treating ovarian cancer patients and the therapeutic potential in developing HDAC6/8 dual inhibitors. |
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| Keywords: | epigenetics HDAC6 HDAC8 ACY-241 PCI-34051 ovarian cancer |
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