siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin

Abstract

Pancreatic cancer is currently one of the deadliest of the solid malignancies, whose incidence and death rates are increasing consistently during the past 30 years. Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides, which are essential for DNA synthesis and replication. In this study, 23 small interfering RNAs (siRNAs) against RRM2, the second subunit of RR, were designed and screened, and one of them (termed siRRM2), with high potency and good RNase-resistant capability, was selected. Transfection of siRRM2 into PANC-1, a pancreatic cell line, dramatically repressed the formation of cell colonies by inducing remarkable cell-cycle arrest at S-phase. When combining with doxorubicin (DOX), siRRM2 improved the efficacy 4 times more than applying DOX alone, suggesting a synergistic effect of siRRM2 and DOX. Moreover, the combined application of siRRM2-loaded lipid nanoparticle and DOX significantly suppressed the tumor growth on the PANC-1 xenografted murine model. The inhibition efficiency revealed by tumor weight at the endpoint of the treatment reached more than 40%. Hence, siRRM2 effectively suppressed pancreatic tumor growth alone or synergistically with DOX. This study provides a feasible target gene, a drug-viable siRNA, and a promising therapeutic potential for the treatment of pancreatic cancer.

EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness

“…Consistent with this idea, we show that pharmacological inhibition and/or siRNA-mediated knockdown of RRM2, which is required for the catalytic activity of the ribonucleotide reductase, is associated with decreased cell growth, G2/M arrest, increased apoptosis and inhibition of cell migration. These findings are consistent with the anti-tumour effects of RRM2 inhibition in pancreatic, 38 cervical 29 and breast cancer 39 as well as in neuroblastoma 40 and glioblastoma. 41 It further suggests that RRM2 may be an interesting therapeutic target in the context of ACC.…”

Silencing of STAT3 via Peptidomimetic LNP-Mediated Systemic Delivery of RNAi Downregulates PD-L1 and Inhibits Melanoma Growth

“…The mechanism of action of small molecular drug and siRNA therapeutics is different. We used ADR dose according to previous reports [22] that confirmed the effectiveness of such control. Dose of DoCh LNP depends on characteristics of siRNA delivery, which is involved in a number of biological processes.…”

Therapeutic siRNA: state of the art

“…Subsequently, LNPs have been increasingly used for siRNA delivery because these vesicles can protect entrapped siRNA from nuclease attack and renal clearance and transport siRNA to targeted tissues and cells. [142][143][144] Canonical siRNA-LNPs comprise similar components, e.g., cationic or ionizable lipids, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), and cholesterol and polyethylene glycol (PEG) lipids. 145 siRNA-LNPs predominantly accumulate in the liver, spleen and kidney after being intravenously injected.…”

“…In particular, the ED 50 of LNPs containing cKK-E12 is as low as 0.002 mg/kg, which is the lowest ED 50 in the liver for all reported LNPs currently. 153 In addition, many firms, including Dicerna Pharmaceuticals (Dicerna), 156 Silence Therapeutics, 157 Sirna Therapeutics, 158 Nitto Denko Corporation, 159 Life Technologies 160 and Suzhou Ribo Life Science, 49,142 have explored proprietary delivery technologies for preclinical and clinical investigations.…”