Abstract | PURPOSE: EXPERIMENTAL DESIGN: RESULTS:
RAD001 markedly inhibited cell proliferation of human ovarian carcinoma cells with high AKT activity (OVCAR10 and SKOV-3), but the effect was minimal in cells with low AKT activity (OVCAR4 and OVCAR5). Sensitivity to RAD001 was independent of p53 expression. RAD001 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase and attenuated the expression of Myc. RAD001 also attenuated the expression of HIF-1 alpha and vascular endothelial growth factor, important factors in angiogenesis and tumor invasiveness. RAD001 enhanced cisplatin-induced apoptosis in cells with high AKT/mTOR activity, with minimal effect in cells with low AKT-mTOR activity. Mouse xenografts of SKOV-3 cells revealed that RAD001 inhibits tumor growth, angiogenesis, and i.p. dissemination and ascites production and prolongs survival. Moreover, treatment with RAD001 significantly enhanced the therapeutic efficacy of cisplatin in vivo. CONCLUSION: These results indicate that RAD001 could have therapeutic efficacy in human ovarian cancers with hyperactivated AKT/mTOR signaling.
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Authors | Seiji Mabuchi, Deborah A Altomare, Mitchell Cheung, Lili Zhang, Poulikos I Poulikakos, Harvey H Hensley, Russell J Schilder, Robert F Ozols, Joseph R Testa |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 13
Issue 14
Pg. 4261-70
(Jul 15 2007)
ISSN: 1078-0432 [Print] United States |
PMID | 17634556
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antineoplastic Agents
- Immunosuppressive Agents
- Everolimus
- Cisplatin
- Sirolimus
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Cell Division
(drug effects)
- Cell Line
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Cisplatin
(therapeutic use)
- Everolimus
- Female
- Humans
- Immunosuppressive Agents
(therapeutic use)
- Kinetics
- Ovarian Neoplasms
- Sirolimus
(analogs & derivatives, therapeutic use)
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