Abstract
Aberrant activation of mTOR contributes to ovarian cancer progression. CC223 is a novel and potent mTOR kinase inhibitor. The current study tested its activity against human ovarian cancer cells. We showed that CC223, at nM concentrations, inhibited survival and proliferation of established/primary human ovarian cancer cells. Further, significant apoptosis activation was observed in CC223-treated ovarian cancer cells. CC223 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in SKOV3 cells. Meanwhile, activation of mTORC1 and mTORC2 was almost completely blocked by CC223. Intriguingly, restoring mTOR activation by introduction of a constitutively-active Akt1 only partially inhibited CC223-induced cytotoxicity in SKOV3 cells. Further studies showed that CC223 inhibited sphingosine kinase 1 (SphK1) activity and induced reactive oxygen species (ROS) production in SKOV3 cells. At last, oral administration of CC223 potently inhibited SKOV3 xenografted tumor growth in nude mice. The results of this study imply that CC223 could be further studied as a potential anti-ovarian cancer agent.
Highlights
Ovarian cancer is one of the leading cancers among women [1,2,3,4]
Further studies showed that the percentage of trypan blue positive (“dead”) SKOV3 cells was significantly increased after CC223 (30–300 nM) treatment (Figure 1C)
These results suggested that CC223 was cytotoxic to cultured human ovarian cancer cells
Summary
Ovarian cancer is one of the leading cancers among women [1,2,3,4]. The incidence of this devastating malignancy has been rising [3, 4]. The current treatment options of ovarian cancer, including the combination of surgery and platinum-based chemotherapy, are very limited [1, 2]. It is estimated that twothird of newly-diagnosed ovarian cancers are advanced diseases, which are remarkably resistant to current treatment [5,6,7]. PI3KAkt-mTOR cascade is often over-expressed and/or overactivated in human ovarian cancer, especially in clear cell carcinoma and endometrioid adenocarcinoma [13]. MTOR represents potentially important therapeutic target for ovarian cancer [14, 15]
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