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HDAC8-Selective Inhibition by PCI-34051 Enhances the Anticancer Effects of ACY-241 in Ovarian Cancer Cells

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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The study described above investigated the effects of combining two HDAC inhibitors, PCI-34051 and ACY-241, in ovarian cancer cells with wild-type and mutant p53. The researchers found that PCI-34051 effectively suppressed cell proliferation in wild-type p53 ovarian cancer cells, and that the combination of PCI-34051 and ACY-241 synergistically repressed cell proliferation, enhanced apoptosis, and suppressed cell migration in ovarian cancer cells with wild-type p53. They also observed that the expression of pro-apoptotic proteins was synergistically upregulated and the expressions of anti-apoptotic proteins and metastasis-associated proteins were significantly downregulated in combination treatment. Moreover, the level of acetyl-p53 at K381 was synergistically upregulated upon combination treatment.

These findings suggest that co-inhibition of HDAC6 and HDAC8 through selective inhibitors could be a promising therapeutic approach for ovarian cancer patients with wild-type p53. The study also highlights the potential of developing HDAC6/8 dual inhibitors as a novel strategy for treating ovarian cancer. However, further research is needed to determine the efficacy and safety of such inhibitors and their potential for clinical use.

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S2012 PCI-34051 PCI-34051 is a potent and specific HDAC8 inhibitor with IC50 of 10 nM in a cell-free assay. It has greater than 200-fold selectivity over HDAC1 and 6, more than 1000-fold selectivity over HDAC2, 3, and 10. PCI-34051 induces caspase-dependent apoptosis.

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