Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells

Wallace H. Mondesire, Weiguo Jian, Haixia Zhang, Joe Ensor, Mien Chie Hung, Gordon Mills, Funda Meric-Bernstam

Research output: Contribution to journalArticle

263 Citations (Scopus)

Abstract

Purpose: The serine-threonine kinase mammalian target of rapamycin has emerged as a potential target for cancer therapy. Rapamycin and rapamycin analogs are undergoing clinical trials and have induced clinical responses in a subgroup of patients. Rapamycin has also been reported to enhance the efficacy of several cytotoxic agents. The aim of this study was to determine the nature of the interactions between rapamycin and chemotherapeutic agents used as first- and second-line agents against breast cancer. Experimental Design: We performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model. Results: In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel- and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu- overexpressing cells, suggesting a potential approach to these poorly behaving tumors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in tumor volume compared with either agent alone in rapamycin-sensitive tumors. Conclusions: Rapamycin potentiates the cytotoxicity of selected chemotherapeutic agents in cell lines sensitive to the effects of rapamycin due to aberrations in the phosphatidylinositol 3′-kinase/Akt pathway, suggesting that combination therapy may be effective in patients selected for aberrations in this pathway.

Original languageEnglish (US)
Pages (from-to)7031-7042
Number of pages12
JournalClinical Cancer Research
Volume10
Issue number20
DOIs
StatePublished - Oct 15 2004
Externally publishedYes

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Sirolimus
Breast Neoplasms
Drug Therapy
Paclitaxel
Carboplatin
gemcitabine
Phosphatidylinositol 3-Kinase
Cell Line
Neoplasms
Protein-Serine-Threonine Kinases
Cytotoxins
Drug Combinations
Caspases
Tumor Burden
Doxorubicin
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. / Mondesire, Wallace H.; Jian, Weiguo; Zhang, Haixia; Ensor, Joe; Hung, Mien Chie; Mills, Gordon; Meric-Bernstam, Funda.

In: Clinical Cancer Research, Vol. 10, No. 20, 15.10.2004, p. 7031-7042.

Research output: Contribution to journalArticle

Mondesire, Wallace H. ; Jian, Weiguo ; Zhang, Haixia ; Ensor, Joe ; Hung, Mien Chie ; Mills, Gordon ; Meric-Bernstam, Funda. / Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 20. pp. 7031-7042.
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AU - Mills, Gordon

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N2 - Purpose: The serine-threonine kinase mammalian target of rapamycin has emerged as a potential target for cancer therapy. Rapamycin and rapamycin analogs are undergoing clinical trials and have induced clinical responses in a subgroup of patients. Rapamycin has also been reported to enhance the efficacy of several cytotoxic agents. The aim of this study was to determine the nature of the interactions between rapamycin and chemotherapeutic agents used as first- and second-line agents against breast cancer. Experimental Design: We performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model. Results: In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel- and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu- overexpressing cells, suggesting a potential approach to these poorly behaving tumors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in tumor volume compared with either agent alone in rapamycin-sensitive tumors. Conclusions: Rapamycin potentiates the cytotoxicity of selected chemotherapeutic agents in cell lines sensitive to the effects of rapamycin due to aberrations in the phosphatidylinositol 3′-kinase/Akt pathway, suggesting that combination therapy may be effective in patients selected for aberrations in this pathway.

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