PKI-587 enhances radiosensitization of hepatocellular carcinoma by inhibiting the PI3K/AKT/mTOR pathways and DNA damage repair.

Abstract

Radiation is an important therapeutic strategy for hepatocellular (HCC). In this study, we evaluated the role of the dual PI3K/mTOR inhibitor, PKI-587, on radiosensitization of HCC and its possible mechanism. MTT, colony formation, flow cytometry, and immunofluorescence were used to analyze the proliferation, cell cycle, formation of residual γ-H2AX foci, and apoptosis of HCC cells. A SK-Hep1 xenograft HCC model was used to assess the effects of PKI-587 in combination with ionizing radiation in vivo. The activation levels of PI3K/AKT/mTOR and DNA damage repair pathways and their downstream effector molecules were detected with Western blot. It was found that PKI-587 sensitized HCC cells to radiation by increasing DNA damage, enhancing G0/G1 cell-cycle arrest, and inducing apoptosis. In vivo, the combination of radiation with PKI-587 significantly inhibited tumor growth. These findings suggest the usefulness of PKI-587 on radiosensitization of HCC cells by inhibiting the PI3K/AKT/mTOR and DNA damage repair pathways. The combination of ionizing radiation and PKI-587 may be a strategy to improve the efficacy of treating HCC.

• Authors: Yinghai Xie, Changwei Liu, Yinci Zhang, Amin Li, Chong Sun, Rui Li, Yingru Xing, Minghong Shi, Qi Wang
• Journal: PloS one (PLoS One) Vol. 16 Issue 10 Pg. e0258817 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 34665844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Morpholines
• Protein Kinase Inhibitors
• Radiation-Sensitizing Agents
• Triazines
• gedatolisib
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Carcinoma, Hepatocellular (metabolism, therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chemoradiotherapy (methods)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Liver Neoplasms (metabolism, therapy)
• Mice
• Morpholines (administration & dosage, pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Radiation-Sensitizing Agents (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Triazines (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays