Abstract 2088 Investigating the conditional lethality of deguelin in blood cancer cells

Cell culture models are crucial to drug discovery because they enable high-throughput screening of chemical compounds based on phenotype or a defined molecular target.However, most anticancer therapeutics fail to translate, owing to limitations of traditional culture models.For example, most chemical screens are performed in traditional culture media such as DMEM or RPMI 1640, which poorly reflect metabolite levels that cells may face in the human body.We previously developed Human Plasma-like Medium (HPLM), a physiologic medium designed to more closely reflect the metabolic composition of human blood.By performing chemical screens in blood cancer cell lines in RPMI and HPLM, we found that nutrient conditions exert a profound influence on drug sensitivity.Among the strongest RPMI-sensitive hits from our screen results was deguelin, a derivative of rotenone that has shown efficacy in multiple cancer types.Deguelin has been suggested to act as an inhibitor of various targets involved in cell signaling pathways and metabolism, including COX2, PI3K, and mitochondrial complex I.To validate this conditional phenotype, we treated K562 chronic myeloid leukemia cells with deguelin in either RPMI or HPLM, and we observed a 30% stronger growth defect in RPMI versus HPLM.We then further recapitulated this conditional deguelin sensitivity across several blood cancer cell lines.Since the cause that may explain why cells show a stronger response to deguelin is not immediately apparent, we are currently using systematic approaches to identify the responsible drug-nutrient interaction.In addition, we are evaluating how deguelin impacts the cellular metabolome to gain unbiased insights into the mechanism of action in blood cancer cells.Overall, we expect that this work will lead to a better understanding of how deguelin inhibits cancer cell growth and could suggest approaches to improve the efficacy of deguelin by exploiting its underlying drug-nutrient interaction.