Abstract 5554: Cisplatin in combination with a potential antiestrogen wedelolactone applied to different gynaecological tumor models

Abstract

Abstract Introduction: Estrogens are found to influence aetiology and progression of endocrine/hormone responsive cancers in patient specific manner. The concept of hormonal manipulations dates back to the last half of twentieth century when tamoxifen was approved by FDA as the first selective estrogen receptor modulator (SERM). A significant decline in mortality rate in breast cancer is attributed partly to advancements in chemotherapy and adjuvant hormone therapy. However, toxicities from mild to life threatening including the risk of endometrial cancer, remain a major problem. Hence the need of new and more effective SERMs remains. Phytoestrogens being structurally similar to human estrogens can mimic their effects in vitro and in vivo. Wedelolactone, a naturally occurring coumestan, has recently emerged as a compound of high interest due to its inhibitory effects on various types of cancer cells. Several studies have demonstrated its potential as antiestrogen in MCF-7, Ishikawa and SKOV-3 cancer cells. Toxic side effects and intrinsic and acquired drug resistance remains a major hurdle in chemotherapy with cisplatin in ovarian cancer. Another place where non/low cytotoxic options would be desired relate to patients with elevated CA-125 (false positive elevations not uncommon in ovarian cancer patients) but without other clinical symptoms, in order to minimize the negative impact on quality of life. The aim of this study was to evaluate wedelolactone in different gynaecological models alone and also in combination with platinum drug cisplatin to determine its suitability in adjuvant or palliative settings. Methods: Cytotoxicity of compounds alone and in binary combination against six cancer cell lines (A2780, A2780cisR, A2780ZD0473R, SKOV-3, MCF-7 and HELA-3) was evaluated using MTT reduction assay and combination index (CI) as a measure of combined drug action was calculated using equations of Chou and Talalay (1984). Results: Cisplatin and wedelolactone showed varied but dose dependent apoptotic effects. CI values were found out to vary showing antagonistic to additive to synergistic effects in different tumor models. Discussion: Wedelolactone considered as a natural apoptotic agent was found to inhibit cell growth irrespective of receptor status. Variations in combined drug action indicate that further studies would be needed to get more insights on signal transduction pathways. Conclusion: Wedelolactone can be further tested in different in vitro and in vivo models in the hope of being useful for patients with recurrent gynaecological cancers (especially ovarian). Citation Format: Sadia Sarwar, Jun Qing Yu, Fazlul Huq. Cisplatin in combination with a potential antiestrogen wedelolactone applied to different gynaecological tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5554. doi:10.1158/1538-7445.AM2015-5554