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.

PI3K/Akt/mTOR would be an important intracellular signal pathway which has found to be over-activated in neoplasia. Here, the combination effect of LY294002 (PI3K inhibitor) and rapamycine (mTOR inhibitor) has evaluated in different human lung cancer cell lines. MTT assay has used to assess the viability of Calu-6, SK-MES-1 and A549 cancer cells. The levels of biochemical markers of apoptosis (activated caspase-3) and cell proliferation (c-Myc and cyclin D1) have evaluated by immunoblotting. The data has shown that blockade of PI3K/Akt cascade with LY294002 (0.1-100 µM) resulted in growth inhibition with IC50 ranging from 7 to 35 µM.LY294002 plus rapamycin (10 nM) significantly enhanced the growth inhibition rate and elevated cleaved caspase-3 in A549 and SK-MES-1 cells. Moreover, such combination therapy had a potent decreasing effect on c-Myc and cyclin D1 protein levels. Taken together, combined inhibition of PI3K/Akt/mTOR signaling has represented a promising treatment strategy for lung cancer but the effectiveness of such combination therapy has been depending on the cancer cell types.