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Eur J Pharmacol ; 898: 173957, 2021 May 05.
Article in English | MEDLINE | ID: mdl-33662352

ABSTRACT

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation in colon cancer contributes to the poor prognosis of the disease and chemoresistance of tumors. New therapies are needed; however, the lack of knowledge of the mechanism of chemoresistance has hindered progress. In this study, we investigated the mechanism of the reduced sensitivity of colon cancer cells to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), and the effects of perifosine, an Akt inhibitor that enhances the cytotoxicity of 5-FU and L-OHP in colon cancer cells harboring the PIK3CA mutation. The use of 5-FU or L-OHP alone or in combination induced significant death of Caco-2 cells (PIK3CA wild type), but only weakly decreased the viability of DLD-1 and SW948 cells harboring the PIK3CA mutation. The use of 5-FU and L-OHP, either alone or in combination, strongly suppressed Akt activation, Survivin, Bcl-2, and Bcl-xL expression, and enhanced Puma, phospho-p53, and p53 expression in Caco-2 cells than in DLD-1 cells. In addition, perifosine enhanced the cytotoxicity of the 5-FU and L-OHP combination, inhibited Akt activation and the expression of Survivin, Bcl-2, and Bcl-xL, and increased the expression of Puma, phospho-p53, and p53 in DLD-1 cells. These results indicate that PIK3CA mutation contributes to reduced sensitivity to 5-FU and L-OHP via Akt activation in colon cancer cells. Perifosine increases the efficacy of 5-FU and L-OHP by suppressing Akt activation. Thus, the use of an Akt inhibitor in combination with 5-FU and L-OHP may be beneficial in colon cancer with cells harboring the PIK3CA mutation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Class I Phosphatidylinositol 3-Kinases/genetics , Colonic Neoplasms/drug therapy , Fluorouracil/pharmacology , Mutation , Oxaliplatin/pharmacology , Phosphorylcholine/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Caco-2 Cells , Class I Phosphatidylinositol 3-Kinases/metabolism , Colonic Neoplasms/enzymology , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Humans , Phosphorylation , Phosphorylcholine/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction
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