Inhibition of phosphatidylinositol 3'-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models.
Phosphatidylinositol 3'-kinase (PI3k) is implicated in a wide array of biological and pathophysiological responses. Thus, inhibiting molecules involved in its signal transduction pathway is a possible means of treating cancer. Our previous studies demonstrated that LY294002, a potent and selective PI3k inhibitor, decreases growth of ovarian carcinoma and ascites formation in an athymic mouse xenogeneic transplant model of ovarian cancer. However, the dose of LY294002 used to decrease tumor growth resulted in significant dermatological toxicity. We demonstrate herein that introduction of an active catalytic subunit of PI3k into an ovarian cancer cell line, and thus activation of the PI3k/AKT pathway, confers resistance to the effects of paclitaxel, one of the major drugs used in ovarian cancer therapy. The resistance to paclitaxel can be reversed in vitro by inhibition of PI3k. Therefore, we evaluated whether combined therapy with paclitaxel and LY294002 would result in increased efficacy and allow utilization of doses of LY294002 that do not induce dermatological toxicity. Two weeks after i.p. inoculation with OVCAR-3 ovarian cancer cells, mice were treated i.p. with LY294002 plus paclitaxel, each three times weekly on alternate days, for 4 weeks. Tumor burden in the LY294002 + paclitaxel, LY 294002 alone, and paclitaxel alone groups was reduced by 80% (P < 0.01), 38% (P < 0.05), and 51% (P < 0.05), respectively, compared with controls. Virtually no ascites developed in the combined treatment group; mean volume of ascites in the controls was 3.7 ml. Treatment with LY294002 alone reduced ascites by 70% (P < 0.01), whereas paclitaxel alone reduced ascites slightly but not significantly. No dermatological lesions or weight loss were observed in any treatment group. In vivo and in vitro morphological studies demonstrated that inhibition of PI3k enhanced paclitaxel-induced apoptosis in the human ovarian cancers. Our data suggest that a combination of a PI3k inhibitor and conventional chemotherapy may provide an effective approach to inhibiting tumor growth and ascites production in ovarian cancer with acceptable side effects.
Hu
Limin
L
Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143-0556, USA.
Hofmann
Judith
J
Lu
Yiling
Y
Mills
Gordon B
GB
Jaffe
Robert B
RB
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014407:Tumor Cells, Cultured
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017239:Paclitaxel