Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells

M. Danielle Bareford, Margaret A. Park, Adly Yacoub, Hossein A. Hamed, Yong Tang, Nichola Cruickshanks, Patrick Eulitt, Nisan Hubbard, Gary Tye, Matthew E. Burow, Paul B. Fisher, Richard G. Moran, Kenneth P. Nephew, Steven Grant, Paul Dent

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Pemetrexed (ALIMTA, Lilly) is a folate antimetabolite that has been approved by the U.S. Food and Drug Administration for the treatment of non-small cell lung cancer and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (Nexavar, Bayer), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K, and/or phosphorylated mTOR, in addition to class III receptor tyrosine kinases such as platelet-derived growth factor receptor beta and VEGF receptors, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.

Original languageEnglish (US)
Pages (from-to)4955-4967
Number of pages13
JournalCancer Research
Volume71
Issue number14
DOIs
StatePublished - Jul 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bareford, M. D., Park, M. A., Yacoub, A., Hamed, H. A., Tang, Y., Cruickshanks, N., Eulitt, P., Hubbard, N., Tye, G., Burow, M. E., Fisher, P. B., Moran, R. G., Nephew, K. P., Grant, S., & Dent, P. (2011). Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Cancer Research, 71(14), 4955-4967. https://doi.org/10.1158/0008-5472.CAN-11-0898