Rapamycin by itself and additively in combination with carboplatin inhibits the growth of ovarian cancer cells.
OBJECTIVE
The current standard treatment for ovarian carcinoma, consisting of surgery followed by chemotherapy with carboplatin and paclitaxel, is fraught with a high rate of recurrences. We hypothesized that targeted inhibition of specific signaling pathways in combination with conventional drugs may increase chemotherapeutic efficacy.


METHODS
We analyzed the expression and activation profiles of various signaling pathways in nine established ovarian cancer cell lines (CAOV-3, ES2, PA-1, SKOV-3, NIHOVCAR3, OV90, TOV112D, A1847, A2780) and 24 freshly procured human ovarian tumors. The PI3 kinase pathway component Akt was frequently overexpressed and/or activated in tumor cells. The effect of several PI3K pathway inhibitors (rapamycin, LY294002, SH-6) and rapamycin in combination with carboplatin on various tumor cell growth characteristics was tested in cell lines and fresh tumor-derived transient monolayer and organ cultures.


RESULTS
Rapamycin by itself and additively with carboplatin inhibited the growth and invasion, and increased the sensitivity to anoikis of most of the ovarian cancer cell lines and fresh tumors. The additive inhibitory effect may be due to enhanced apoptosis as demonstrated by Poly-ADP-Ribose Polymerase (PARP) cleavage and Annexin V staining in cells treated with both rapamycin and carboplatin.


CONCLUSIONS
Rapamycin in combination with standard chemotherapeutic agents may improve the efficiency of ovarian cancer treatment.
Schlosshauer
Peter W
PW
Department of Pathology, The Mount Sinai School of Medicine, New York, NY 10029, USA.
Li
Wei
W
Lin
Kai-Ti
KT
Chan
Joseph L-K
JL
Wang
Lu-Hai
LH
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000008:administration & dosage / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
D016190:Carboplatin; D002867:Chromones; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C516024:SH-6 compound; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one