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Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor

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Abstract

The type I insulin-like growth factor receptor (IGF1R) contributes to cancer cell biology. Disruption of IGF1R signaling alone or in combination with cytotoxic agents has emerged as a new therapeutic strategy. Our laboratory has shown that sequential treatment with doxorubicin (DOX) and anti-IGF1R antibodies significantly enhanced the response to chemotherapy. In this study, we examined whether inhibition of the tyrosine kinase activity of this receptor family would also enhance chemotherapy response. Cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF1R and insulin receptor (InsR) kinase activity and downstream activation of ERK1/2 and Akt in MCF-7 and LCC6 cancer cells. PQIP inhibited both monolayer growth and anchorage-independent growth in a dose-dependent manner. PQIP did not induce apoptosis, but rather, PQIP treatment was associated with an increase in autophagy. We examined whether sequential or combination therapy of PQIP with DOX could enhance growth inhibition. PQIP treatment together with DOX or DOX followed by PQIP significantly inhibited anchorage-independent growth in MCF-7 and LCC6 cells compared to single agent alone. In contrast, pre-treatment with PQIP followed by DOX did not enhance the cytotoxicity of DOX in vitro. Furthermore, OSI-906, a PQIP derivative, inhibited IGF-I signaling in LCC6 xenograft tumors in vivo. When given once a week, simultaneous administration of OSI-906 and DOX significantly enhanced the anti-tumor effect of DOX. In summary, these results suggest that timing and duration of the IGF1R/InsR tyrosine kinase inhibitors with chemotherapeutic agents should be evaluated in clinical trials. Long-term disruption of IGF1R/InsR may not be necessary when combined with cytotoxic chemotherapy.

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Abbreviations

IGF1R:

The type I insulin-like growth factor receptor

PQIP:

Cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine

InsR:

Insulin receptor

DOX:

Doxorubicin

ERK:

Extracellular-signal-regulated kinases

PI3K:

The phosphatidylinositol 3-kinase

TKIs:

Tyrosine kinase inhibitors

PARP:

Poly (ADP) ribose polymerase

mTOR:

Mammalian target of rapamycin

LC3:

Microtubule-associated protein 1 light chain 3

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Acknowledgments

We thank Dr. Do-Hyung Kim for constructive technical advice on autophagy experiments. We thank Dr. Elizabeth Buck from OSI Pharmaceuticals for providing OSI-906 and valuable discussions in the writing of the manuscript. This work was supported by National Institutes of Health R01CA74285 to DY and National Cancer Institute Cancer Center Support Grant P30077598.

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Authors and Affiliations

  1. Masonic Cancer Center, University of Minnesota, MMC 806, 420 Delaware St SE, Minneapolis, MN, 55455, USA

    Xianke Zeng, Hua Zhang, Annabell Oh, Yan Zhang & Douglas Yee

  2. Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA

    Xianke Zeng & Douglas Yee

  3. Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA

    Hua Zhang & Douglas Yee

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  1. Xianke Zeng
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Correspondence to Douglas Yee.

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Zeng, X., Zhang, H., Oh, A. et al. Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor. Breast Cancer Res Treat 133, 117–126 (2012). https://doi.org/10.1007/s10549-011-1713-x

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  • DOI: https://doi.org/10.1007/s10549-011-1713-x

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