lys01 and Adenocarcinoma--Clear-Cell

Clear cell ovarian carcinoma (CCOC) is an aggressive form of epithelial ovarian cancer that exhibits low response rates to systemic therapy and poor patient outcomes. Multiple studies in CCOC have revealed expression profiles consistent with increased hypoxia, and our previous data suggest that hypoxia is correlated with increased autophagy in CCOC. Hypoxia-induced autophagy is a key factor promoting tumor cell survival and resistance to therapy. Recent clinical trials with the molecular-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib have demonstrated limited activity. Here, it was evaluated whether the hypoxia-autophagy axis could be modulated to overcome resistance to sunitinib. Importantly, a significant increase in autophagic activity was found with a concomitant loss in cell viability in CCOC cells treated with sunitinib. Pharmacologic inhibition of autophagy with the lysosomotropic analog Lys05 inhibited autophagy and enhanced sunitinib-mediated suppression of cell viability. These results were confirmed by siRNA targeting the autophagy-related gene

Topics: Adenocarcinoma, Clear Cell; Aminoquinolines; Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Female; Humans; Indoles; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Polyamines; Pyrroles; Sunitinib; Xenograft Model Antitumor Assays