Abstract
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 on multiple myeloma (MM) cells of oleil hydroxytyrosol (HTOL), a synthetic fatty ester of natural hydroxytyrosol with oleic acid. HTOL reduced the viability of various human MM cell lines (HMCLs), even when co-cultured with bone marrow stromal cells, triggering ER stress, UPR and apoptosis, while it was not cytotoxic against healthy peripheral blood mononuclear cells or B lymphocytes. Whole-transcriptome profiling of HTOL-treated MM cells, coupled with protein expression analyses, indicate that HTOL antagonizes key survival pathways for malignant plasma cells, including the undruggable IRF4–c-MYC oncogenic axis. Accordingly, c-MYC gain- and loss-of-function strategies demonstrate that HTOL anti-tumor activity was, at least in part, due to c-MYC targeting. Taken together, these findings underscore the anti-MM potential of HTOL, providing the molecular framework for further investigation of HTOL-based treatments as novel anti-cancer agents.
Highlights
Multiple myeloma (MM) is a B cell malignancy of clonal plasma cells (PCs) accumulating in the bone marrow (BM), characterized by a complex genomic and epigenomic landscape [1,2,3]
HTOL, the chemical structure of which is reported in Figure 1A, was obtained by a standardized procedure as reported in Materials and Methods
We tested the in vitro anti-tumor activity of HTOL in MM cells co-cultured with MM patient-derived bone marrow stromal cells (BMSCs), known to sustain growth and to promote the chemoresistance of MM cells
Summary
Multiple myeloma (MM) is a B cell malignancy of clonal plasma cells (PCs) accumulating in the bone marrow (BM), characterized by a complex genomic and epigenomic landscape [1,2,3]. Scientific interest in natural drugs and their derivatives has recently grown due to the limitations and toxicity of conventional therapies in comparison to the safety of naturalproduct-derived compounds. In this regard, the biological activities of plant extracts have been extensively linked to their content in various molecules, such as polyphenols, flavonoids and terpenoids, known to elicit therapeutic effects against cancer, cardiovascular and neurodegenerative diseases. The combination of plant extracts with anticancer drugs has often shown synergistic therapeutic efficacy by sensitizing malignant cells to chemotherapy, and/or overcoming drug resistance in various cancer types [5,6], including MM [7,8,9]. A major source of anti-tumor polyphenols is extra virgin olive oil (EVOO), the polyphenolic fraction of which includes simple phenols (tyrosol and hydroxytyrosol), secoiridoids (oleuropein, oleocanthal and oleacein) and lignans [9,10,11,12,13]
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