Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma.

Abstract

Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual γ-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2-M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC.

• Authors: Tongxin Liu, Quanquan Sun, Qi Li, Hua Yang, Yuqin Zhang, Rong Wang, Xiaoshan Lin, Dong Xiao, Yawei Yuan, Longhua Chen, Wei Wang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 2 Pg. 429-39 (Feb 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25504751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• H2AX protein, human
• Histones
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyridazines
• Quinolines
• Sulfonamides
• Triazines
• omipalisib
• gedatolisib
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Carcinoma
• Cell Cycle Checkpoints (drug effects, radiation effects)
• Cell Line, Tumor
• Cell Movement (drug effects, radiation effects)
• Cell Proliferation (drug effects, radiation effects)
• Disease Progression
• Histones (metabolism)
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Morpholines (therapeutic use)
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms (enzymology, pathology)
• Neoplasm Invasiveness
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyridazines
• Quinolines (pharmacology, therapeutic use)
• Radiation Tolerance (drug effects)
• Radiation, Ionizing
• Signal Transduction (drug effects, radiation effects)
• Sulfonamides (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Treatment Outcome
• Triazines (therapeutic use)
• Xenograft Model Antitumor Assays