Abstract 5470: Safe and targeted anticancer therapeutic efficacy of a novel antioxidant-conjugated difluoro-diarylidenyl-piperidone (HO-3867) against ovarian cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.5470-5470
• Main Authors: Kuppusamy, Periannan, Selvendiran, K., Tong, L., Bratasz, A., Kuppusamy, ML, Trigg, NJ, Rivera, BK, Kálai, T., Hideg, K.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-5470

The anticancer efficacy of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) against ovarian cancer is reported. Studies were performed using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1 and OVCAR3, as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 demonstrated a preferential toxicity towards ovarian cancer cells, while sparing healthy cells. HO-3867 induced G2/M cell-cycle arrest in A2780 cells by modulating cell-cycle regulatory molecules p53, p21, p27, cdk2 and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in STAT3 (Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor (VEGF), suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian tumors in a dosage-dependent manner without any apparent toxicity. We further analyzed of xenografted tumor tissues showed that HO-3867 inhibits pSTAT3 (Tyr705 and Ser727) and Jak1 and increased apoptotic markers of cleaved caspase-3 and PARP. The results clearly showed that HO-3867 exhibited significant cytotoxicity towards ovarian cancer cells by inhibiting the JAK/STAT3-signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5470.