CUDC-101 Overcomes Arsenic Trioxide Resistance Via Caspase-Dependent PML-Rarα Degradation in Acute Promyelocytic Leukemia

While arsenic trioxide (ATO) treatment has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, many high-risk APL patients who fail to achieve a complete molecular remission or relapse become resistant to ATO. Studies have suggested that HDAC inhibitors (HDACi) have been targeted as promising agents for the treatment of several cancers. In this study, a novel pan-HDACi 7-(4-(3-Ethynylphenylamino)-7- methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) was used to tentatively to treat hematologic disease for the first time. The CCK-8 assay demonstrate that CUDC-101 exerts much stronger anti-proliferative effects than ATO in APL and ATO-resistant APL cell lines. Previous experiments on cell proliferation inhibition prompted investigation of whether CUDC-101 could induce apoptosis in APL and ATO-resistant APL cells. Then the results of apoptosis assay strongly support CUDC-101 as an effective apoptosis inducer that induced apoptotic cell death in both APL and ATO-resistant APL cell lines, more effectively than ATO. Our data also demonstrate that CUDC-101 is a novel drug that has a negligible cytotoxic effect on non-cancerous cell lines including normal CD34⁺ cells and BMSCs from APL patients. Mechanistically, we conclude that CUDC-101 directly induce hyperacetylation of histone 3, which subsequently lead to the activation of caspase 3, the activated-caspase 3 cleaves the PML-RARα fusion protein subsequently facilitates APL and ATO-resistant APL cells undergoing apoptosis. The precise mechanism of CUDC-101-induced degradation of PML-RARα remains unclear. Yet the apoptosis inducing effect of CUDC-101 offers a potent therapeutic advantage of CUDC-101 and its role in overcoming APL warrants further validation in patient-derived samples in future studies. Finally, using a NB4 xenograft mouse model, we demonstrated that CUDC-101 significantly represses leukemia development in vivo compared with ATO. These findings suggest that the CUDC-101 is efficient in inhibiting tumor growth in vivo and performs better than ATO. To the best of our knowledge, this is the first report that CUDC-101 functions as HDACi and has potential therapeutic value for the treatment of both APL and relapsed APL with ATO resistance in vitro and in vivo. In conclusion, these results suggested that CUDC-101 can serve as a potential candidate drug for APL, particularly for ATO-resistant APL.