5th Asia-Pacific Summit on Cancer Therapy
Zhejiang University, China
Title: Dual inhibition of Cdc7 and Cdk9 by PHA-767491 suppresses hepatocarcinoma synergistically with 5-fluorouracil
Biography: Xi Chen
Activation of checkpoint kinase 1 (Chk1) is essential in chemo resistance of hepatocarcinoma (HCC) to5-fluorouracil (5-FU) and other anti metabolite family of drugs. In this study, we demonstrated that PHA-767491, a dual inhibitor of two cell cycle checkpoint kinases, cell division cycle kinase 7 (Cdc7) and cyclin-dependent kinase 9 (Cdk9) has synergistic antitumor effect with 5-FU to suppress human HCC cells both in vitro and in vivo. Compared with the sole use of each agent, PHA-767491 in combination with 5-FU exhibited much stronger cytotoxicity and induced significant apoptosis manifested by remarkably increased caspase 3 activation and poly (ADP-Ribose) polymerase (PARP) fragmentation in two HCC cell lines BEL-7402 and Huh7. PHA-767491 directly counteracted the 5-FU-induced phosphorylation of Chk1, a substrate of Cdc7 and decreased the expression of the anti-apoptotic protein myeloid leukemia cell 1 (Mcl1), a downstream target of Cdk9. In tumor tissues sectioned from nude mice HCC xenografts, administration of PHA-767491 also decreased Chk1 phosphorylation and increased in situ cell apoptosis. Our study suggests that PHA-767491 could enhance the efficacy of 5-FU by inhibiting Chk1 phosphorylation and down-regulating Mcl1 expression through inhibition of Cdc7 and Cdk9, thus combinational administration of PHA-767491 with 5-FU could be potentially beneficial to patients with advanced and resistant HCC.