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A. Torossian et al.
liposome-based miR-34a mimic is the first miRNA mimic to be used in clinical studies and has already been evaluated in phase I clinical trials in patients with advanced solid tumors.45 The combination of miR-34a mimics with other anti-cancer agents could thus represent
a novel way to counteract therapeutic failure. In addition, we carried out experiments with the BH3-mimetic venetoclax. We treated KARPAS-299 ALCL cells with venetoclax concentrations (from 10nM to 25μM), which were described by Souers et al. for cells with high and low
AB
C
Figure 6. miR-34-mediated BCL2 downregulation potentiates the antitumoral effects of crizotinib in vivo. (A) ALK-positive KARPAS-299 cells, transfected with either a negative control microRNA (miR-Neg) or miR-34a mimics (miR-34a), were injected subcutaneously into the left or right flank of 16 NOD/SCID mice, respectively. Eight of these mice received oral crizotinib (2.5 mg/kg) for 22 days, while the remaining eight received vehicle. Tumor volume was evaluated over time by caliper measurements and was reported as means±Standard Error of Mean (SEM). Statistical analysis was performed by two-way ANOVA with Bonferroni correction; ****P≤0.0001. (B) Representative tumors resected from mice xenografted with miR-Neg or miR-34a cells that received either vehicle or crizotinib treatment (scale in cm). Their weights are indicated (mg). (C) Micrographs showing Hematoxylin & Eosin (HE), anti-LC3B and anti-P62 stainings of excised miR-Neg or miR-34a tumors that in addition received either vehicle or crizotinib treatment (scale bars: 20 μm, inset HE staining 5000 μm). Arrows indicate cells with phenotypic hallmarks of nuclear piknosis and general cellular fragility.
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haematologica | 2019; 104(7)