Department of Oncology and Hemato-Oncology, University of Milano, 20122 Milano, Italy.
Hematology Unit, Fondazione Cà Granda IRCCS, Ospedale Maggiore Policlinico, 20122 Milano, Italy.
Int J Mol Sci. 2021 Oct 28;22(21):11639. doi: 10.3390/ijms222111639.
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.
橄榄油中的多酚具有多种生物活性。最近，人们对这些化合物进行了化学修饰，以提高它们在不同病理环境下的治疗活性，包括癌症。本文描述了合成天然羟基酪醇（HTOL）与油酸的脂肪酸酯——油酰基羟基酪醇（HTOL）对多发性骨髓瘤（MM）细胞的体外作用。HTOL 降低了多种人 MM 细胞系（HMCL）的活力，即使与骨髓基质细胞共培养时也是如此，从而引发内质网应激、未折叠蛋白反应和细胞凋亡，而对健康外周血单核细胞或 B 淋巴细胞没有细胞毒性。HTOL 处理的 MM 细胞的全转录组谱分析，加上蛋白质表达分析，表明 HTOL 拮抗恶性浆细胞的关键存活途径，包括不可成药的 IRF4-c-MYC 致癌轴。相应地，c-MYC 获得和缺失功能策略表明，HTOL 的抗肿瘤活性至少部分归因于 c-MYC 靶向。综上所述，这些发现强调了 HTOL 对 MM 的潜在作用，为进一步研究基于 HTOL 的治疗方法作为新型抗癌药物提供了分子框架。
