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Journal article
Suppression of AKT anti-apoptotic signaling by a novel drug candidate results in growth arrest and apoptosis of hepatocellular carcinoma cells
PloS one, v 8(1), pp e54595-e54595
2013
PMCID: PMC3552860
PMID: 23355882
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Suppression of AKT anti-apoptotic signaling by a novel drug candidate results in growth arrest and apoptosis of hepatocellular carcinoma cells
- Creators
- Andrea Cuconati - Hepatitis B FoundationCourtney Mills - Hepatitis B FoundationCally Goddard - Hepatitis B FoundationXianchao Zhang - Drexel UniversityWenquan Yu - Tianjin UniversityHaitao Guo - Drexel UniversityXiaodong Xu - Hepatitis B FoundationTimothy M Block - Drexel University
- Publication Details
- PloS one, v 8(1), pp e54595-e54595
- Publisher
- Public LIbrary of Science (PLOS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000314021500092
- Scopus ID
- 2-s2.0-84872808323
- Other Identifier
- 991019168159304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology