Abstract
Abstract The present studies sought to determine whether the anti-folate pemetrexed (Alimta) and the sphingosine-1-phosphate receptor modulator FTY720 (Fingolimod, Gilenya) interacted to kill tumor cells. FTY720 and pemetrexed interacted in a greater than additive fashion to kill breast, brain and colorectal cancer cells. Loss of p53 function weakly enhanced the toxicity of FTY720 whereas deletion of activated RAS strongly or expression of catalytically inactive AKT facilitated killing. In contrast, expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the toxic interaction between FTY720 and pemetrexed. Indeed, combined drug exposure reduced the activity of AKT, p70 S6K and mTOR and activated JNK and p38 MAPK. Expression of activated forms of AKT, p70 S6K and mTOR or inhibition of JNK and p38 MAPK suppressed the toxic interaction between FTY720 and pemetrexed. Treatment of cells with FTY720 and pemetrexed increased the numbers of autophagosomes in cells that correlated with increased LC3 processing and increased p62 levels. Knock down of ATG5 or Beclin1 suppressed autophagosome formation and cell killing by the drug combination. Sorafenib was previously shown to potently interact with pemetrexed to kill tumor cells. Sorafenib significantly enhanced the lethality of [FTY720 + pemetrexed] treatment in vitro and in vivo. Collectively our findings argue that pemetrexed, sorafenib and FTY720 could be a novel adjunct modality for breast cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Jane L. Roberts, Seyedmehrad Tavallai, Andrew Poklepovic, Laurence Booth, Paul Dent. Gilenya and Alimta interact to kill breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3503. doi:10.1158/1538-7445.AM2015-3503
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