Abstract 5449: Novel seleno-biotin compound inhibits viability of and induces reactive oxygen species (ROS)-mediated apoptosis in ovarian cancer cells

Abstract

Abstract Ovarian cancer is one of the most common cancers in women and even with the currently available treatment options, including surgery, radiation, and chemotherapy, it caused 13,940 deaths in US alone in 2020. Thus, there is a continuous need for developing novel approaches for the treatment of ovarian cancer, particularly drug resistant ovarian cancer, as ovarian cancer most adversely affects the lives patients. Here in, we have designed seleno-biotin derivatives as potential therapeutics for ovarian cancer. The rational for designing these hybrid small molecules is two fold: (i) The biotin receptors are up-regulated in various carcinomas including ovarian cancer cells while being expressed at low levels in normal cells. Due to the high affinity of biotin towards BR, biotin has been used as a conjugate for several targeted imaging, sensing, and delivery in vitro and in vivo. (ii) Organoselenium compounds with appropriate selenium moieties have shown therapeutic efficacy in several pre-clinical cancer models. Therefore, we designed several analogs of biotin by conjugating selenium moieties connected through ester, selenoester, or amide functionalities and their cytotoxicities were assessed using four different ovarian cancer cell lines. Ester-linked biotin-selenocyanate compound 2, out of the other analogs, in direct comparison to biotin alone, more effectively reduced the cell viability (IC50 9.8-18.5 µM against all the tested cell lines) and induced apoptosis in ovarian cancer cells in dose dependent manner as demonstrated by the cell viability assay. It showed three times more potency (IC50 14.08 µM) than standard drugs 5-FU (IC50 48.4 µM) and cisplatin (IC50 41.0 µM) against drug-resistant Hey A8 cancer cells and three times more activity with an IC50 value of 9.8 µM as compared to 5-FU (IC50 25.92 µM) against ES-2 cells. The above findings were supported by trypan blue dye exclusion assay, Annexin V/7-AAD, Caspase 3/7 apoptosis assays and Western blotting of apoptotic proteins. Compound 2 effectively caused cell cycle arrest of the treated OVCAR-3 cells in S-phase of the cell cycle, thus causing regulatory changes in the cell cycle proteins, as evident by Western blotting. In addition, compound 2 redox cycles was demonstrated by DCFDA based reactive oxygen species estimation. These experiments demonstrate that selenium modified biotin which contains a covalently attached redox cycling selenide group has the potential for human therapeutic applications against ovarian and other cancers over-expressing biotin receptors. Citation Format: Asif Raza, Amandeep Singh, Amin Shantu, L. Mallory Boylan, Julian E. Spallholz, Arun Sharma. Novel seleno-biotin compound inhibits viability of and induces reactive oxygen species (ROS)-mediated apoptosis in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5449.