Antiproliferative and proapoptotic effect of the MLK/JNK inhibitor CEP-1347 in hepatocellular carcinoma

Background: Sorafenib is the only systemic agent approved for the therapy of hepatocellular carcinoma (HCC). However, in spite of its efficacy, the investigation of alternative therapeutic targets is urgently required. JNK is overexpressed in the majority of HCC and chemical induction of HCC is prevented by JNK inhibition. Notably, expression of JNK was recently shown to predict a poor response to sorafenib. Nevertheless, since no JNK inhibitor is currently undergoing investigation as therapy of HCC, JNK remains a largely unexploited therapeutic target. CEP-1347 is a MLK/JNK inhibitor originally designed to prevent the progression of Parkinson's disease, and underwent extensive Phase 3 clinical investigation proving save and well tolerated. We aimed at assessing the potential efficacy of this compound as therapy of HCC.

Methods: the effect of CEP-1347 was assessed in liver cancer cell lines by viability assays, FACS-based analysis of cell cycle and apoptosis and by western blot. In vivo, its effect was assessed in a model of xenograft tumor induction by daily intraperitoneal injections of CEP-1347 or vehicle.

Results: Administration of CEP-1347 in nanomolar range led to a dramatic loss of cell viability and enhanced the antiproliferative effect of sorafenib by causing G2/M cell cycle arrest and apoptosis. Concomitantly, caspase cleavage and the downregulation of apoptosis regulators Mcl-1 and Bcl-2 were observed. In vivo CEP-1347 strongly inhibited tumor growth of Huh7 cells (Figure).

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Conclusions: We provide preclinical in vitro and in vivo data showing the antitumor activity of CEP-1347 and propose the utilization of this compound as experimental therapy of hepatocellular carcinoma.