Oleil hydroxytyrosol (HTOL) exerts anti-myeloma activity by antagonizing key survival pathways in malignant plasma cells

Polyphenols from olive oil are endowed with several biological activities. Chemical modifications have been recently applied to these compounds to improve their therapeutic activity in different pathological settings, including cancer. Herein, we describe the in vitro effects elicited by oleil hy-droxytyrosol (HTOL), a synthetic fatty ester of natural hydroxytyrosol with oleic acid, on multiple myeloma (MM) cells. HTOL reduced the viability of different human MM cell lines (HMCLs), triggering UPR, ER stress and apoptosis, while it was not cytotoxic against healthy peripheral blood mononuclear cells. Microarray-based whole transcriptome profiling of HTOL-treated MM cells, coupled with protein expression analyses, indicates that HTOL antagonizes molecular pathways key for malignant plasma cell survival, including the undruggable IRF4-c-MYC oncogenic axis. c-MYC gain- and loss-of-function experiments indicate that HTOL anti-tumor activity was, at least in part, due to c-MYC targeting. Taken together, these findings underscore the anti-MM activity of HTOL, providing the molecular framework for further investigation of HTOL-based treatments as novel anti-cancer agents. JJN3 Human myeloma Cell Line (HMCL) was treated with HTOL (5.0 µM , 24h). Global transcript expression profiles of HTOL treated JJN3 were investigated in comparison to control cells. Duplicates were used for each condition.