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Title: Pharmacologic synergy between dual phosphoinositide-3-kinase and mammalian target of rapamycin inhibition and 5-Fluorouracil in PIK3CA mutant gastric cancer cells
Authors: Bhattacharya, B. 
Akram, M.
Balasubramanian, I. 
Tam, K.K.Y.
Koh, K.X.
Yee, M.Q.
Soong, R. 
Keywords: 5-Fluorouracil
Combination index
Thymidylate synthase
Issue Date: 1-Jan-2012
Citation: Bhattacharya, B., Akram, M., Balasubramanian, I., Tam, K.K.Y., Koh, K.X., Yee, M.Q., Soong, R. (2012-01-01). Pharmacologic synergy between dual phosphoinositide-3-kinase and mammalian target of rapamycin inhibition and 5-Fluorouracil in PIK3CA mutant gastric cancer cells. Cancer Biology and Therapy 13 (1) : 74-82. ScholarBank@NUS Repository.
Abstract: Phosphoinositide-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors are an emerging class of anti-cancer agents. Here, we tested the hypothesis that the dual PI3K/mTOR inhibitor, PI103, could synergize with the chemotherapeutic agent, 5-fluorouracil (5-FU) by inhibiting E2F1, thymidylate synthase (TS) and enhancing DNA damage. Drug combination effects were assessed in gastric cancer cells using the median-effect equation. The specific effects of inhibition of E2F1 and PIK3CA were examined by siRNA, and mTOR by rapamycin exposure. Protein expression and apoptosis pre- and posttreatment was measured using standard methods. PI103 and 5-FU was synergistic in 3 out of 5 gastric cancer cell lines tested. Synergy was associated with PI3KCA mutation, reduced TS and E2F1 protein levels, increased H2AX phosphorylation and apoptosis. E2F1 siRNA enhanced sensitivity to 5-FU only in cells displaying synergy. Excess thymidine exposure converted synergism to antagonismin all cells. Inhibition of PI3K and mTOR alone enhanced 5-FU cytotoxicity in only 2 out of 3 cell lines that displayed synergy each. In AGS cells, PI3K inhibition alone enhanced 5-FU sensitivity as much as dual PI3K/mTOR inhibition. In HGC27 cells, dual inhibition increased 5-FU sensitivity more than single PI3K or mTOR inhibition. Combined PI103 and 5-FU treatment reduced in vivo tumor growth more than treatment with single agents. PI3K/mTOR inhibitors can enhance 5-FU cytotoxicity in vitro and in vivo, especially in PIK3CA mutant tumor cells. Dual, rather than single, PI3K/mTOR inhibitors may combine better with 5-FU due to cellular heterogeneity in sensitivity to PI3K and mTOR inhibition. © 2012 Landes Bioscience.
Source Title: Cancer Biology and Therapy
ISSN: 15384047
DOI: 10.4161/cbt.13.1.18437
Appears in Collections:Staff Publications

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