Oleil Hydroxytyrosol (HTOL) Exerts Anti-Myeloma Activity by Antagonizing Key Survival Pathways in Malignant Plasma Cells

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.

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

“…MM cells stably expressing the luciferase transgene or DNM1L gene were obtained as previously described [ 21 ]. The packaging of each construct in pseudoviral particles was performed in HEK-293Ta cells, which were co-transfected with 10 µg of the lentiviral Lenti-hCMV-ORF-N-HA-IRES-puro for Homo sapiens DNM1L (or the empty vector, both from Transomic), along with 10.0 µg of p-CMV-VSVG, and 4.0 µg of Delta8.9 plasmids.…”

GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma

“…Cell viability was evaluated by using the Cell Titer Glo (CTG) assay (Promega, Madison, WI, USA), as reported [ 30 ]. MM cells were seeded in 24-well plates, treated with different concentrations of G-1 alone or in combination with G-15 or Z-VAD, and collected at different time points.…”

Beneficial Effect of Olive Oil and Its Derivates: Focus on Hematological Neoplasm

“…An interesting new research was investigated in recent years, based on the use of phenolic compounds, particularly hydroxytyrosol, in various human multiple myeloma (MM) cell lines. A study conducted by Todoerti et al [56] demonstrates that HTOL (a synthetic fatty ester of natural hydroxytyrosol with oleic acid) reduces the viability of human myeloma cell lines (HMCLs) at low micromolar doses, even in the presence of bone marrow stromal cells (BMSCs), without exhibiting cytotoxicity towards healthy peripheral blood mononuclear cells (PBMCs) or B-lymphocytes [56,[84][85][86][87]. Moreover, HTOL was found to down-regulate Interferon signaling pathways, which are pivotal in controlling various immune responses, both innate and adaptive [88].…”

“…IRF4's N-terminal DNA binding domain (DBD) contains a helixloop-helix motif crucial for identifying specific DNA sequences related to the interferonstimulated response element [89]. Notably, IRF4 translocation to actively transcribed genomic areas in some multiple myeloma (MM) patients is associated with carcinogenicity and overexpression, yet it confers a survival benefit in MM without translocations or amplifications [56,89]. Several studies have underscored the essential role of IRF4 in MM cell survival, with genetic knockdown of IRF4 or targeting the tumor suppressor miR-125b being fatal to MM cells [90,91].…”

“…HTOL was found to block the IRF4 signaling pathway, leading to an arrest in the development of myeloma cells. Importantly, due to the higher expression of molecular targets identified by the IRF4-cMYC axis in MM cells, HTOL-based treatments exhibit low toxicity [56]. This study suggests that targeting the IRF4-c-MYC axis, which remains challenging due to the lack of clinically useful targeted treatments, may offer novel therapeutic approaches not only for MM but also for other c-MYC-dependent cancer types [56].…”