SiRNA-Mediated RRM2 Gene Silencing Combined with Cisplatin in the Treatment of Epithelial Ovarian Cancer In Vivo: An Experimental Study of Nude Mice

Abstract

Introduction: We aimed to explore small interfering (si)RNA silencing of ribonucleotide reductase M2 (RRM2) gene combined with cisplatin for the treatment of human ovarian cancer in nude mice models of subcutaneous transplantation of tumor cells.Methods: After conventional cultivation of human ovarian cancer cell line SKOV3 in vitro, SKOV3 cells were injected into the right back of nude mice by subcutaneous injection to establish the subcutaneous tumor models. Twenty-four tumor-burdened rats were randomly divided into four groups (n=6): siRNA group, siRNA in combination with cisplatin group, cisplatin group, and control group. Intraperitoneal injection of cisplatin and subcutaneous injection of siRNA were performed weekly. Tumor volume was measured, and tumor growth inhibition rate was calculated. RRM2 expression at the mRNA and protein levels was detected by reverse transcription-polymerase chain reaction and immunohistochemistry.Results: In the siRNA group, the tumor volume and tumor growth inhibition rate were 249.60±20.46 mm³ and 36.39%, respectively. The tumor growth inhibition rate and tumor volume were significantly different between the siRNA and control groups (p<0.05). In the cisplatin group, the tumor volume and tumor growth inhibition rate were 249.86±12.46 mm³ and 41.10%, respectively. The tumor growth inhibition rate and tumor volume were significantly different between the cisplatin and control groups (p<0.05). In the siRNA + cisplatin group, the tumor volume reduced to 180.84±16.25 mm³ and the tumor growth inhibition rate was increased to 64.33%, which were significantly different compared with the control group (p<0.01). Significant downregulation of RRM2 mRNA and protein expression in the tumor tissues was detected by reverse transcription polymerase chain reaction and immunohistochemistry assay (p<0.05).Discussion: siRNA alone or combined with cisplatin can effectively inhibit the growth of human ovarian cancer in nude mice models of subcutaneous transplantation of tumor cells. RRM2 gene silencing may be a potential treatment regimen for ovarian cancer in future.

Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

“…Overall, CP induces DNA damage in cancer cells and suppresses cancer cell proliferation and viability. The combination of CP with other chemotherapeutic agents has shown great potential in cancer therapy [49][50][51][52][53][54].…”

Interplay between altered metabolism and DNA damage and repair in ovarian cancer

“…[ 40 ] Other studies have found that the combination of RRM2 knockdown and cisplatin is synergistic in mouse models. [ 94 ] Similarly, inhibition of folate synthesis via methotrexate or berberine reduces the viability of platinum‐resistant ovarian cancer cells. [ 95 ] While many of the classical anti‐metabolites have failed in clinical trials due to on‐target toxicity, advances in the understanding of nucleotide synthesis [ 96 ] may provide new opportunities to revisit inhibition of this pathways to exacerbate DNA damage‐inducing agents.…”

Progress in Natural Compounds/siRNA Co-delivery Employing Nanovehicles for Cancer Therapy

“…In ovarian cancer cells, silencing of RRM2 via siRNA induces DNA damage and inhibits their repair. This, in turn, increases the sensitivity of cancer cells to cisplatin chemotherapy …”

“…This, in turn, increases the sensitivity of cancer cells to cisplatin chemotherapy. 94 The signaling networks responsible for proliferation, metastasis, radioresistance and chemoresistance of cancer cells have been reported in previous studies. Targeting molecular pathways is important in suppressing the aggressive behavior of cancer cells and in promoting their responses to chemotherapy and radiotherapy.…”