Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer fatalities worldwide, with limited treatment options and five year survival rates of between <5 and 15%. To address this medical need, we conducted a screen of a drug-like small molecule library for HCC-selective cytotoxins. We report here the identification of a disubstituted aminothiazole termed HBF-0079, with remarkable selective toxicity for HCC-derived cell lines versus non-HCC liver lines and most other cancer lines. HBF-0079 caused irreversible growth arrest and apoptosis of the HCC lines Huh7, Hep3B, HepaRG as well as the hepatoblastoma line HepG2, with CC50 values from ∼0.7−7.7 µM, while more than 45 µM was needed to achieve CC50 values for the immortalized normal hepatocyte lines THLE-2 and PH5CH. Of the sixty cancer lines from the National Cancer Institute panel, only five exhibited >50% growth inhibition by HBF-0079. In Huh7 cells, HBF-0079 induced cell cycle arrest in G1 and concomitant apoptosis, and its effects were irreversible after removal of the compound. These observations corroborate a loss of AKT phosphorylation at the mTORC2-targeted residue S473, with concurrent loss of phosphorylation of the mTORC1 targets SK6 and 4EBP1 in Huh7 but not PH5CH cells. Finally, growth of Hep3B-derived tumors in a murine xenograft model was significantly repressed by the compound through either systemic or intratumoral administration of formulated HBF-0079. The potential for development of this drug candidate is discussed.
Highlights
In the US, primary liver cancer is currently the fifth most common cause of cancer deaths among men, and ninth among women, with the numbers increasing yearly
Compounds that reduced MTT signal by more than 50% after three days of treatment at 10 mM were counterscreened against the immortalized human hepatocyte (HC)-derived cell line THLE-2
The distinct gene expression patterns of clinically indistinguishable Hepatocellular carcinoma (HCC) tumors suggests that the molecular mechanisms of HCC establishment and maintenance vary widely [37,38,39,40,41], underlying the difficulty in chemotherapeutic treatment of this cancer; ostensibly, different agents would act on different pathways, and would only be effective in a subset of HCC cases
Summary
In the US, primary liver cancer is currently the fifth most common cause of cancer deaths among men, and ninth among women, with the numbers increasing yearly. Liver transplantation is used with success, but is contraindicated in cases where the primary tumor has metastasized Other treatments, such as ablation by ethanol injection into the solid tumor mass, focused ultrasound, and radiation, are practiced but rarely result in complete remission [8]. Standard cancer drugs such as doxorubicin, cisplatin, and 5fluorouracil have been used with anecdotal success, but are limited in effectiveness [8]
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