Abstract 2238: Novel sylibin analogues target ovarian cancer EMT-Wnt/β-catenin resistance pathways

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.2238-2238
• Main Authors: Amawi, Haneen A., Hussein, Noor, Fetcenkoa, Aubry, Alnafisah, Rawan, Chandrabose, Karthikeyan, Manivannan, Elangovan, Trivedi, Piyush, Tiwari, Amit K.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-2238

Ovarian cancer (OC) is one of most lethal malignancies in woman reproductive tract. The OC diagnosed in advanced stage (III-IV) patients is highly aggressive and relapses back in over 80% patient after initial response to chemotherapy. Currently used chemotherapies are limited due to significant adverse/toxic effects, a narrow therapeutic index, and development of multidrug resistance mediated by the epithelial-to-mesenchymal transition (EMT) and cancer cell membrane efflux transporters. It is presumed that an ideal anti-OC drug that has diverse mechanisms, would inhibit several key cell-survival signaling and resistance pathways when combined with conventional chemotherapy (paclitaxel and cisplatin). Silybin, a polyphenolic flavonoid, has previously shown to inhibit metastasis by inhibition of EMT pathways and bypass other drug resistance factors i.e. efflux transporters in ovarian cancer both in vitro and in vivo. However, clinical use of silybin is limited due to their poor absorption and low bioavailability and poor potency. To overcome this, we designed and synthesized 11 silybin derivatives using molecular modeling, computer aided drug design, structure activity relationship, natural product lead optimization and ring disjunction approaches. In our preliminary findings, we found the lead molecule (15k) to have a cytotoxicity (IC50&lt1µM) with potency more than 200-fold compared to silybin (IC50~150µM). The 15k was found to be around 10-fold selective in OC cells (OV2008, A2780) compared to normal ovarian cells. Additionally, compared to other cancer cells belonging to prostate, breast, lung, 15k was (3-6)-fold selective in OC cells (OV2008, A2780). The 15k produced synergistic activity and potentiated the cytotoxic effects of platinum (cisplatin), anthracyclines (doxorubicin) and taxane (paclitaxel) anticancer agents. While 15k also reversed the drug resistance mediated by ABC-efflux transporters to paclitaxel and doxorubicin. Mechanistically, the cytotoxic effect of lead compound 15k, as determined by using molecular biology assays, was found to be due to inhibition of apoptosis, tubulin inhibition, and inhibition of stemness pathways (Wnt-β-catenin-EMT). The 15k had significant anti-metastatic effects as shown by their inhibition of migration and invasion potential on OC cells. In silico findings suggest that pharmacokinetic [PK] profiles of these compounds are favorable compared to silybin. Further in vivo PK/pharmacodynamic studies are underway t