Dual Inhibition of Cdc7 and Cdk9 by PHA-767491 Suppresses Hepatocarcinoma Synergistically with 5-Fluorouracil

• Published in: Current cancer drug targets Vol. 15; no. 3; p. 196
• Main Authors: Li, Wei, Zhao, Xiao-Le, Shang, Shi-Qiang, Shen, Hong-Qiang, Chen, Xi
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2015
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line, Tumor - drug effects; Checkpoint Kinase 1; Cyclin-Dependent Kinase 9 - antagonists & inhibitors; Cyclin-Dependent Kinase 9 - metabolism; Female; Fluorouracil - administration & dosage; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy - methods; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Phosphorylation - drug effects; Piperidones - administration & dosage; Piperidones - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyrroles - administration & dosage; Pyrroles - pharmacology; Xenograft Model Antitumor Assays
• DOI: 10.2174/1568009615666150212112753

Activation of checkpoint kinase 1 (Chk1) is essential in chemoresistance of hepatocarcinoma (HCC) to 5-fluorouracil (5-FU) and other antimetabolite 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 fragmentation in HCC cells. 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, 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.