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

Shikha Gaur; Linling Chen; Lixin Yang; Xiwei Wu; Frank Un; Yun Yen

doi:10.1016/j.canlet.2011.06.005

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.

Authors

Shikha Gaur¹, Linling Chen, Lixin Yang, Xiwei Wu, Frank Un, Yun Yen

Affiliation

¹ Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.

PMID: 21764510
DOI: 10.1016/j.canlet.2011.06.005

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
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases
DNA Topoisomerases, Type II
Cisplatin
Sirolimus