Evidence of novel miR-34a-based therapeutic approaches for multiple myeloma treatment

Abstract

MiR-34a acts as tumor suppressor microRNA (miRNA) in several cancers, including multiple myeloma (MM), by controlling the expression of target proteins involved in cell cycle, differentiation and apoptosis. Here, we have investigated the combination between miR-34a and γ-secretase inhibitor (γSI), Sirtinol or zoledronic acid (ZOL) in order to enhance the inhibitory action of this miRNA on its canonical targets such as Notch1 and SIRT1, and on Ras/MAPK-dependent pathways. Our data demonstrate that miR-34a synthetic mimics significantly enhance the anti-tumor activity of all the above-mentioned anti-cancer agents in RPMI 8226 MM cells. We found that γSI enhanced miR-34a-dependent anti-tumor effects by activating the extrinsic apoptotic pathway which could overcome the cytoprotective autophagic mechanism. Moreover, the combination between miR-34a and γSI increased the cell surface calreticulin (CRT) expression, that is well known for triggering anti-tumor immunological response. The combination between miR-34a and Sirtinol induced the activation of an intrinsic apoptotic pathway along with increased surface expression of CRT. Regarding ZOL, we found a powerful growth inhibition after enforced miR-34a expression, which was not likely attributable to neither apoptosis nor autophagy modulation. Based on our data, the combination of miR-34a with other anti-cancer agents appears a promising anti-MM strategy deserving further investigation.

Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

“…Although the trial was closed early due to serious immune-mediated adverse effects that resulted in the death of four patients, the dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy [ 172 ]. The combination treatment with miR-34a has been shown to enhance the anti-tumor activity of other anti-cancer agents (γ-secretase inhibitor, sirtinol and zoledronic acid) in MM cells, through various mechanisms [ 173 ]. The γ-secretase inhibitor enhanced miR-34a-dependent anti-tumor effects by activating an extrinsic apoptotic pathway, whereas the combination of miR-34a and sirtinol, induced the activation of an intrinsic apoptotic pathway [ 173 ].…”

“…The combination treatment with miR-34a has been shown to enhance the anti-tumor activity of other anti-cancer agents (γ-secretase inhibitor, sirtinol and zoledronic acid) in MM cells, through various mechanisms [ 173 ]. The γ-secretase inhibitor enhanced miR-34a-dependent anti-tumor effects by activating an extrinsic apoptotic pathway, whereas the combination of miR-34a and sirtinol, induced the activation of an intrinsic apoptotic pathway [ 173 ].…”

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway

“…To our knowledge, miRNAs involved in regulation of PD-L1 in MM have yet to be described; however, considering the overlap with some miRNAs known to be involved in MM, such as the miR-15 family, the miR17~ 92 cluster, miR-21, miR-34a, or miR-106b [ 118 , 119 ], it stands to reason that some miRNAs regulating PD-L1 expression could be involved in MM. MiR-34 therapy has been shown to result in increased survival in vitro and in MM animal models [ 120 , 121 ].…”

The Non-Coding RNA Landscape of Plasma Cell Dyscrasias

“…Notably, the potential of miR-221 as therapeutic target was proved using the specific LNA-i-miR-221 inhibitor, that showed anti-MM efficacy and favorable PK profile upon systemic delivery in vivo [109]. On the other hand, enforced expression of tumor suppressor miR-34a exerted a strong anti-MM activity through BCL2, CDK6, and NOTCH1 targeting both in vitro an in vivo in the SCID-synth-hu model of MM, which recapitulates the disease within its BM milieu [110,111]. Likewise, the inverse correlation of miR-125b levels with IRF4, an "Achilles' heel" of MM, showed that this specific miRNA, differently from other hematologic malignancies, has tumor suppressor activity in MM [112].…”