Abstract 3808: Targeting cholesterol for increased chemotherapy efficacy

The PI3K-AKT pro-survival signal present in most cancer cells is the major obstacle to effective chemotherapies. However, most chemotherapeutics targeting the PI3K-AKT pathway have undesirable side effects. β-cyclodextrin (βCD) and its derivatives were found to diminish PI3K-AKT activities in cancer cells with limited side effects. Treatments of cultured cells with βCD depleted cholesterol from the plasma membrane abolishing their coated pits. Even though growth factors such as IGF1 and insulin activated their receptors, their signals were not transduced to downstream signals such as PI3K-AKT pro-survival pathway. The inhibitory effect lasted as long as βCD was present in the medium. Injected into a mouse, βCD attenuated IGF1-induced blood glucose drop for several hours. In the absence of PI3K-AKT pro-survival signal, cells became sensitized to mitochondria dependent cell death such as Bcl2 antagonists ABT-263 in many epithelial cells and Fas and TRAIL in type II cells. In mice carrying human cancer cells, the addition of HPβCD (a derivative of βCD) to the 2-deoxyglucose & ABT-263 combination therapy, and to the TRAIL therapy improved their efficacies. Citation Format: Ryuji Yamaguchi. Targeting cholesterol for increased chemotherapy efficacy. [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 3808. doi:10.1158/1538-7445.AM2015-3808