Background Resveratrol exerts inhibitory effects on ovarian cancer cells while its underlying mechanism and critical molecular target(s) have been lesser known. effects of resveratrol on human ovarian cancer cells in terms of remarkable G1 phase accumulation increased apoptosis fraction and concurrent suppression of Wnt Notch and STAT3 signaling as well as their downstream cancer-related gene expression. Treatments with Wnt Notch or STAT3 selective inhibitor revealed that only Notoginsenoside R1 AG490 a JAK-specific inhibitor inhibits OVCAR-3 and CAOV-3 cells in the extent as similar as that of resveratrol. Conclusion Our results suggest the significance of STAT3 Rabbit Polyclonal to p300. activation in the maintenance and survival of ovarian cancer cells. The activated STAT3 signaling is the critical molecular target of resveratrol. Resveratrol would be a promising candidate in the management of ovarian cancers especially the ones with resistance to conventional therapeutic agents. Keywords: Ovarian cancer Resveratrol Signal transduction pathway STAT3 Selective inhibitor Gene expression Introduction Ovarian cancer (OC) is one of the commonest female malignancies and accounts for the leading death rates among the gynecologic cancers [1 2 The main reasons of the poor prognosis of OCs are the delayed diagnosis due to the very subtle symptoms at the early stage of ovarian carcinogenesis [3] and the easiness of spreading through blood dissemination [4] and peritoneal transplantation [5 6 Surgical treatment is the first choice to remove ovarian cancers if the tumours are well-differentiated in relative small sizes and/or confined to the ovary [7 8 However the patients with advanced OCs have to be operated for debulking the disease and then treated by standard chemotherapy such as a dose-dense paclitaxel and carboplatin regimen [9 10 Although the therapeutic outcome has been improved by more accurate staging of the disease and more aggressive surgical excision of tumor spots in the abdomen the overall survival rates remain unoptimistic because of the frequent tumour recurrence and severe toxic effects of the anticancer agents [11-13]. For these reasons it would be necessary to explore more efficient and lesser toxic agent(s) with clearer molecular targets for better adjuvant management of ovarian cancers. Resveratrol (3 5 4 has been regarded as a nontoxic polyphenolic compound that can be found in grapes berries peanuts and red wine [14]. A body of evidence has demonstrated that resveratrol is able to inhibit the growth of many cancers such as bladder cancer breast cancer and primary brain tumors [15-17]. Increasing data have shown that resveratrol can exert its biological effects on cancer cells by altering multiple molecular targets [18 19 For example it suppresses growth and induces apoptosis of human medulloblastoma cells accompanied with inhibition of STAT3 activation and transcription [18]. More importantly the anticancer doses (100 μM to 200 μM) of resveratrol have little harmful effect on glial cells and neurons in central nervous system and transitional epithelial cells of the urinary Notoginsenoside R1 bladder [15 17 19 The inhibitory effects of resveratrol on ovarian cancer cells have been documented as well [20 21 Although some studies have shown certain molecular alterations in resveratrol-treated ovarian cancer cells such as down-regulation of Akt/GSK signaling [22] and VEGF expression [23] the critical event(s) among those alterations remains largely unknown. It is therefore necessary to address this point by comprehensively analyzing the statuses of ovarian cancer-related signaling pathways as well as their downstream genes. Some signaling transduction pathways are found to be activated in the processes of ovarian carcinogenesis and play favorable roles Notoginsenoside R1 in cell growth and survival [24-26]. For instance hyperactive Jaks/STAT3 signaling promote enhanced colony-forming ability motility and migration of cisplatin-resistant ovarian cancer cells [27]. Similarly Wnt/beta-catenin pathway also contributes to the proliferation of human ovarian cancer cell [28] and inhibition of Notch signaling a key pathway for ovarian cancer stem cells sensitizes tumors to platinum therapy [25]. The data obtained from other cancer systems reveal that Notoginsenoside R1 resveratrol can inhibit the signaling pathways mediated by STAT3.