Gene interactions and pathways from curated databases and text-mining
Cancer Biol Ther 2012, PMID: 22336586

Pharmacologic synergy between dual phosphoinositide-3-kinase and mammalian target of rapamycin inhibition and 5-fluorouracil in PIK3CA mutant gastric cancer cells.

Bhattacharya, Bhaskar; Akram, Mohamed; Balasubramanian, Indirikumar; Tam, Kimberley K Y; Koh, King X; Yee, Mei Q; Soong, Richie

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 post-treatment was measured using standard methods. PI103 and 5-FU was synergistic in 3/5 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 antagonism in all cells. Inhibition of PI3K and mTOR alone enhanced 5-FU cytotoxicity in only 2/3 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.

Diseases/Pathways annotated by Medline MESH: Stomach Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

E2F1 → PI3K/mTOR: " 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 "

E2F1 → PI3K/mTOR: " 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 "

PI3K/mTOR → PI3K: " In AGS cells, PI3K inhibition alone enhanced 5-FU sensitivity as much as dual PI3K/mTOR inhibition "

PI3K/mTOR → PI3K: " In AGS cells, PI3K inhibition alone enhanced 5-FU sensitivity as much as dual PI3K/mTOR inhibition "

PI3K/mTOR → PI3K: " In AGS cells, PI3K inhibition alone enhanced 5-FU sensitivity as much as dual PI3K/mTOR inhibition "

Manually curated Databases

No curated data.