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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.

Related Products

Cat.No. Product Name Information
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.

Related Targets

Apoptosis related HDAC