Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression.

Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G(1) phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27(Kip1); and knockdown of p27(kip1) with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity.

McDonald GT ，Sullivan R ，Paré GC ，Graham CH ... -  《-》

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 M ，Esmaeili-Mahani S 《-》

[Combined inhibition of PI3K and MEK has synergistic inhibitory effect on the proliferation of cisplatin-resistant ovarian cancer cells].

Liu Y ，Chen X ，Luo Z 《-》

Phosphatidylinositol 3-kinase inhibitor LY294002 suppresses proliferation and sensitizes doxorubicin chemotherapy in bladder cancer cells.

Phosphatidylinositol 3-kinase (PI3K)-AKT signaling is a well-characterized pathway involved in the control of cell proliferation, apoptosis and oncogenesis. LY294002 is a commonly used pharmacologic inhibitor which acts at the ATP-binding site of the PI3K enzyme, thus selectively inhibiting the PI3K-AKT nexus. The purpose of the present study was to examine whether PI3K inhibited by LY294002 had an effect on human bladder cancer cells. After treatment with LY294002, MTT assay, chemosensitivity test, colony formation assay, apoptosis assay and Western blot analysis were conducted in EJ cells. EJ cells treated with LY294002 showed significant AKT phosphorylation suppression in a dose-response manner. Also, PI3K/AKT signaling inhibitor LY294002 suppressed cell proliferation and enhanced the chemosensitivity of doxorubicin in human bladder cancer EJ cells. Furthermore, LY294002 increased cell apoptosis to doxorubicin. The augmentation of doxorubicin with PI3K inhibitor LY294002 may resolve the multidrug resistance of bladder cancer, and this may be a new strategy for achieving tolerance for chemotherapeutic agents in bladder cancer therapy.

Wu D ，Tao J ，Xu B ，Qing W ，Li P ，Lu Q ，Zhang W ... -  《-》

Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy.

Tsurutani J ，West KA ，Sayyah J ，Gills JJ ，Dennis PA ... -  《CANCER RESEARCH》