Phosphatidylinositol 3-kinases inhibitor LY294002 potentiates the cytotoxic effects of doxorubicin, vincristine, and etoposide in a panel of cancer cell lines.
Many novel therapeutic approaches to overcome chemoresistance have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway. PI3K is a known stress response pathway which is involved in the regulation of cell survival, apoptosis, and growth. Inhibition of this pathway may possibly restore or augment the effectiveness of chemotherapy. Using three human malignant cell lines, we examined the effects of LY294002 (PI3K inhibitor) on chemotherapeutic agent-induced apoptosis and cytotoxicity. An antimicrotubule agent vincristine, a topoisomerase II inhibitor etoposide, and a DNA cross-linking agent doxorubicin were used accompanied with LY294002. Cell viability was determined by MTT assay, and the induction of apoptosis was assessed by immunoblotting of caspase-3. Blocking the PI3K/Akt cascade with a PI3K inhibitor LY294002 (10 μM) increased the cytotoxic effect of vincristine and doxorubicin on SK-OV-3 cell line. Furthermore, LY294002 showed a greater promoting effect in etoposide- and doxorubicin-induced cytotoxicity on MDA-MB-468 and A549 cells. The quantity of cleaved caspase-3 in cancer cells that had combination therapy was increased compared with that in the cells treated with each drug alone. We suggest that inhibitors of the PI3K/Akt pathway in combination with chemotherapeutic agents may induce cell death effectively and be a potent modality to treat various types of cancer. The effectiveness of such combination therapy is depending to the used cell line and class of anticancer drug.
['Badinloo|Marzieh|M|', 'Esmaeili-Mahani|Saeed|S|']
D000970:Antineoplastic Agents D000971:Antineoplastic Combined Chemotherapy Protocols D017209:Apoptosis D001943:Breast Neoplasms D053148:Caspase 3 D045744:Cell Line, Tumor D002470:Cell Survival D002867:Chromones D004317:Doxorubicin D004357:Drug Synergism D004791:Enzyme Inhibitors D005047:Etoposide D005260:Female D006801:Humans D008175:Lung Neoplasms D009025:Morpholines D010051:Ovarian Neoplasms D019869:Phosphatidylinositol 3-Kinases D000081082:Phosphoinositide-3 Kinase Inhibitors D051057:Proto-Oncogene Proteins c-akt D014750:Vincristine
chemotherapy human malignant cell lines PI3K inhibitor cell death