Suppression of AKT Anti-Apoptotic Signaling by a Novel Drug Candidate Results in Growth Arrest and Apoptosis of Hepatocellular Carcinoma Cells

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.

Lycopene Metabolite, Apo-10′-Lycopenoic Acid, Inhibits Diethylnitrosamine-Initiated, High Fat Diet–Promoted Hepatic Inflammation and Tumorigenesis in Mice

“…PI-3K/Akt signaling in human HepG2 hepatoma cells plays a key role in basal cell proliferation that correlates with increased cyclin D1 (55), and in insulin growth factor receptor-mediated DNA replication (55). Small molecules that abrogate Akt phosphorylation in human HCC cell lines caused irreversible growth arrest and apoptosis (56), indicating the importance of Akt-mediated signaling for the growth and survival of transformed cells within liver tumors. In the present study, APO10LA significantly reduced hepatic surface tumor volume by 65% (Table 1).…”

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

“…The PI3K/Akt signalling pathway is related to HCC cell proliferation 16 . Previous reports have shown that ARRB1 mediates Akt phosphorylation to activate PI3K/Akt signalling in response to a variety of stimuli 28 .…”

“…Akt is frequently induced in human HCC samples, and overexpression of Akt in mouse livers results in tumour development 14,15 . Disruption of the PI3K/Akt axis correlates with HCC growth arrest and/or apoptosis 16 . The mechanism of TNF-a-induced Akt activation in HCC is still unclear, and the interaction between TNF-a and Akt in HCC needs to be further investigated A family of seven-transmembrane domain G-protein-coupled receptors (GPCRs) constitutes the largest known superfamily for signal transduction and transmission 17 .…”

Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents

“…There are only a handful of small molecules that have been reported to possess selective toxicity to liver cancer versus normal liver cells, making the aminothiazoles described here unusual. 13–19 Moreover, none of the other liver cancer-selective small molecules have been further progressed, to our knowledge. These compounds are mainly phenolic or flavonoid natural products which were isolated from herbs.…”