Abstract
Olive oil contains different biologically active polyphenols, among which oleacein, the most abundant secoiridoid, has recently emerged for its beneficial properties in various disease contexts. By using in vitro models of human multiple myeloma (MM), we here investigated the anti-tumor potential of oleacein and the underlying bio-molecular sequelae. Within a low micromolar range, oleacein reduced the viability of MM primary samples and cell lines even in the presence of bone marrow stromal cells (BMSCs), while sparing healthy peripheral blood mononuclear cells. We also demonstrated that oleacein inhibited MM cell clonogenicity, prompted cell cycle blockade and triggered apoptosis. We evaluated the epigenetic impact of oleacein on MM cells, and observed dose-dependent accumulation of both acetylated histones and α-tubulin, along with down-regulation of several class I/II histone deacetylases (HDACs) both at the mRNA and protein level, providing evidence of the HDAC inhibitory activity of this compound; conversely, no effect on global DNA methylation was found. Mechanistically, HDACs inhibition by oleacein was associated with down-regulation of Sp1, the major transactivator of HDACs promoter, via Caspase 8 activation. Of potential translational significance, oleacein synergistically enhanced the in vitro anti-MM activity of the proteasome inhibitor carfilzomib. Altogether, these results indicate that oleacein is endowed with HDAC inhibitory properties, which associate with significant anti-MM activity both as single agent or in combination with carfilzomib. These findings may pave the way to novel potential anti-MM epi-therapeutic approaches based on natural agents.
Highlights
Multiple myeloma (MM) is a clonal B cell malignancy characterized by the accumulation of tumor plasma cells (PCs) in the bone marrow (BM), where different cell types establish a complex microenvironment that supports survival, proliferation and drug-resistance of the malignant clone.The last few years have witnessed a rapid development of drugs for the treatment of this malignancy, leading to increased extent and frequency of response and to the improvement in median overall survival of patients
Regarding the epigenetic-modulating effects, it has natural agents, by targeting DNMTs [25], histone deacetylases (HDACs) [26] or non-coding-RNAs [27], may revert aberrant been demonstrated that several natural agents, by targeting DNMTs [25], HDACs [26] or nonepigenetic patterns implicated in the pathogenesis of human neoplasias, including MM [2]
Since previous findings indicated that bortezomib-evoked transcriptional repression of HDACs by Sp1 occurs in a caspase 8-dependent fashion [18], we investigated whether oleacein effect on Sp1 could be mediated by caspase 8
Summary
The last few years have witnessed a rapid development of drugs for the treatment of this malignancy, leading to increased extent and frequency of response and to the improvement in median overall survival of patients. Despite such therapeutic advancements, MM eventually evolves into a drug-resistant phase leading to patients’ death [1]. Cancers 2019, 11, 990 on new therapeutic options, as single agents or in combination with established anti-MM drugs In this regard, natural compounds have recently emerged as novel chemopreventive and/or therapeutic tools able to target oncogenic pathways involved in the pathogenesis of human malignancies. Several natural compounds from various plants, fungi and marine organisms have been shown to target epigenetic events underpinning tumorigenesis, such as DNA methylation, histone modifications (methylation, acetylation and phosphorylation), and non-coding RNAs [3], known to be deeply dysregulated and representing valuable therapeutic targets in MM [2]
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