Synthetic miR-34a Mimics as a Novel Therapeutic Agent for Multiple Myeloma:In VitroandIn VivoEvidence

Abstract

Purpose Deregulated expression of microRNAs (miRNAs) has been demonstrated in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a. Experimental Design Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo. Results Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6 and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in SCID mice. The anti-MM activity of lipidic-formulated miR-34a was further demonstrated in vivo in two different experimental settings: i) SCID mice bearing non-transduced MM xenografts; and ii) SCID-synth-hu mice implanted with synthetic 3D scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity. Conclusions Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.

MicroRNAs as regulators of bone homeostasis and bone metastasis

“…51 Similarly, miR-34a was found to decrease in vivo tumor growth of human MM cells, potentially through the regulation of BCL2, CDK6 and NOTCH1. 52 MiR-15a and miR-16, which are frequently suppressed in MM, inhibit proliferation and growth of MM both in vitro and in vivo. 53 In addition, both miRNAs were shown to directly regulate VEGF-A expression during MM progression, inhibiting angiogenesis and decreasing miRNAs as regulators of bone homeostasis and metastasis B Ell and Y Kang tumor growth in vivo.…”

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

“…[169,170] PCL scaffolds containing miR34a mimics were fabricated as a "neutral-lipid-emulsion" delivery system and then implanted in the flank of severe combined immunodeficiency (SCID) mice. [169] In vivo results corroborated in vitro experiments where miR-34a mimics confirmed significant anti-proliferative effects, apoptotic activity and control of gene expression, thus proving evidence of the antitumoral activity of miR-34a in preclinical scaffold systems of this disease.…”

“…[169,170] PCL scaffolds containing miR34a mimics were fabricated as a "neutral-lipid-emulsion" delivery system and then implanted in the flank of severe combined immunodeficiency (SCID) mice. [169] In vivo results corroborated in vitro experiments where miR-34a mimics confirmed significant anti-proliferative effects, apoptotic activity and control of gene expression, thus proving evidence of the antitumoral activity of miR-34a in preclinical scaffold systems of this disease. Zhou et al [170] have most recently described a proof-of-concept study outlining a multifunctional supramolecular hydrogel formed by the conjugate of the peptic sequence GRGDS with biaryltetrazole (Tet(II)-GRGDS) for the delivery of miR-34a into encapsulated U87 cells, a human primary glioblastoma cell line.…”

Target Therapy in Platinum-Refractory/Resistant Ovarian Cancer: From Preclinical Findings to Current Clinical Practice

“…In different studies in vitro and in vivo, in different tumors, miR-34 replacement/overexpression induced apoptosis and reduced cellular migration, proliferation and tumor growth [125,126]. therapy.…”