Inhibitors of mTOR overcome drug resistance from topoisomerase II inhibitors in solid tumors

Cancer Lett. 2011 Dec 1;311(1):20-8. doi: 10.1016/j.canlet.2011.06.005. Epub 2011 Jun 29.

Abstract

The present study was performed to investigate the possible role of mTOR inhibitors in restoring chemosensitivity to adriamycin/cisplatin and elucidate the underlying mechanism. Combining adriamycin/cisplatin with torisel synergistically inhibited the cell proliferation in human oropharyngeal carcinoma cell line KB and its multidrug-resistant subclone KB/7D. Combining adriamycin and torisel inhibited the phosphorylation of 4EBP-1 and p70S6K, the proteins involved in mTOR pathway, increased expression of γH2AX indicative of DNA damage, triggered cell cycle arrest at G2/M and apoptosis. We conclude that chromatin decondensation by DNA damage provided an easy access for torisel to block the translation of proteins essential for DNA repair thereby restoring the chemosensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • DNA Damage
  • DNA Repair
  • DNA Topoisomerases, Type II / metabolism*
  • Doxorubicin / administration & dosage
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Eukaryotic Initiation Factors / metabolism
  • Everolimus
  • Female
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / enzymology
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • Phosphorylation / drug effects
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Topoisomerase II Inhibitors / administration & dosage
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Eukaryotic Initiation Factors
  • Topoisomerase II Inhibitors
  • temsirolimus
  • Doxorubicin
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • DNA Topoisomerases, Type II
  • Cisplatin
  • Sirolimus