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Suppression of AKT anti-apoptotic signaling by a novel drug candidate results in growth arrest and apoptosis of hepatocellular carcinoma cells
Journal article   Open access   Peer reviewed

Suppression of AKT anti-apoptotic signaling by a novel drug candidate results in growth arrest and apoptosis of hepatocellular carcinoma cells

Andrea Cuconati, Courtney Mills, Cally Goddard, Xianchao Zhang, Wenquan Yu, Haitao Guo, Xiaodong Xu and Timothy M Block
PloS one, v 8(1), pp e54595-e54595
2013
DOI: https://doi.org/10.1371/journal.pone.0054595
PMID: 23355882
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1371/journal.pone.0054595View
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - enzymology Carcinoma, Hepatocellular - pathology Cell Cycle Checkpoints - drug effects Hep G2 Cells Humans Liver Neoplasms - drug therapy Liver Neoplasms - enzymology Liver Neoplasms - pathology Mechanistic Target of Rapamycin Complex 1 Mechanistic Target of Rapamycin Complex 2 Mice Multiprotein Complexes - metabolism Phosphorylation - drug effects Proteins - metabolism Proto-Oncogene Proteins c-akt - metabolism Signal Transduction - drug effects Thiadiazoles - pharmacology TOR Serine-Threonine Kinases - metabolism Xenograft Model Antitumor Assays
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.

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Web of Science research areas
Oncology
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