HiF-1α siRNA and Cisplatin in Combination SuppressTumor Growth in a Nude Mice Model of Esophageal Squamous Cell Carcinoma

Abstract

Introduction: The esophagus squamous cell carcinoma (ESCC) is one of the most deadly malignances, and a current challenge is the development of effective therapeutic agents. Our present work addressed the effect of HIF-1α siRNA alone or in combination with cisplatin on the growth of ESCC in nude mice. Materials and Methods: Xenografts were established by inoculating ESCC TE-1 cells in nude mice, and transplanted tumors were treated with HIF-1α siRNA, cisplatin alone or together. Growth was assessed by measuring tumor volume. HIF-1α mRNA and protein expression were detected using RT-PCR and immunohistochemistry, respectively. Apoptosis of ESCC TE-1 cells was analyzed by flow cytometry. Results: In our nude mice model, HIF-1α siRNA effectively inhibited the growth of transplanted ESCC, downregulating HIF-1α mRNA and protein expression, and inducing ESCC TE-1 cell apoptosis. Notably when combinated with cisplatin, HIF-1α siRNA showed synergistic interaction in suppressing tumor growth. Furthermore, the proportion of apoptotic cells in HIF-1α siRNA plus cisplatin group was significantly higher than that in cisplatin or HIF-1α siRNA-treated groups (P<0.05). Conclusions: Down-regulated HIF-1α expression induced by siRNA could effectively suppress the growth of transplanted ESCC in vivo. HIF-1α siRNA could enhance the cytotoxicity of cisplatin, which suggests that a combination of these two agents may have potential for therapy of advanced ESCC.

Genetic Variations in the HIF1A Gene Modulate Response to Adjuvant Chemotherapy after Surgery in Patients with Colorectal Cancer

“…Previous studies have found that HIF-1α overexpression indicates unfavorable prognosis and may serve as an potential prognostic factor in several cancers (Zhong et al, 1999;Marton et al, 2012;Wan et al, 2012;Li et al, 2013;Luan et al, 2013;Zhang et al, 2013;), including colon, breast , gastric, lung , skin, ovarian, pancreatic, prostate, and renal carcinomas. Furthermore, down-regulated HIF-1α expression in transplanted esophageal squamous cell carcinoma in vivo could enhance the cytotoxicity of cisplatin (Liao et al, 2012). One of the major mechanisms underlying the association of HIF-1α with patients' outcomes in these cancers may be that HIF-1α or its target genes can induces chemoresistance in many types of cancer.…”

Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer

“…43,44 In the present study, we observed increased chemosensitivity to THP in HIF-1a shRNA-treated cells, compared with NC shRNA treated or untreated cells, supporting the notion that the combination of gene therapy and chemotherapy may be a new hope for TNBC treatment. 45 Recently, a constitutively active HIF-1a transgene mediated by adenovirus has been tested as a therapeutic strategy in no-option critical limb ischemia patients in a phase I dose-escalation study and was shown well tolerated. 46 Based on our results from the present study, we speculate that stable downregulation of HIF-1a by lentivirus could be a novel effective and safe gene therapy approach to TNBC treatment.…”

Hypoxia-Inducible Factor 1 Promoter-Induced JAB1 Overexpression Enhances Chemotherapeutic Sensitivity of Lung Cancer Cell Line A549 in an Anoxic Environment

“…Down-regulated HIF-1α expression induced by siRNA could effectively suppress the growth of transplanted ESCC in vivo. HIF-1αsiRNA could enhance the cytotoxicity of cisplatin, which suggests that a combination of these two agents may have potential for therapy of advanced ESCC (Liao et al, 2012). Several studied have shown that HIF-1/HRE can be successfully used as hypoxia-regulated tool for gene therapy in a hypoxic environment (Ruan et al, 2001;Post and Van Meir, 2001).…”