Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model

Abstract

Different routes for the in vivo administration of synthetic siRNA complexes targeting lung tumors were compared, and siRNA complexes were administered for the inhibition of hypoxia-inducible factor (HIF-1a and HIF-2a). Intravenous jugular vein injection of siRNA proved to be the most effective means of targeting lung tumor tissue in the Lewis lung carcinoma (LLC1) model. In comparison, intraperitoneal injection of siRNA was not suitable for targeting of lung tumor and intratracheal administration of siRNA exclusively targeted macrophages. Inhibition of HIF-1a and HIF-2a by siRNA injected intravenously was validated by immunohistofluorescent analysis for glucose-transporter-1 (GLUT-1), a well-established HIF target protein. The GLUT-1 signal was strongly attenuated in the lung tumors of mice treated with siRNA-targeting HIF-1a and HIF-2a, compared with mice treated with control siRNA. Interestingly, injection of siRNA directed against HIF-1a and HIF-2a into LLC1 lung tumor-bearing mice resulted in prolonged survival. Immunohistological analysis of the lung tumors from mice treated with siRNA directed against HIF-1a and HIF2a displayed reduced proliferation, angiogenesis and apoptosis, cellular responses, which are known to be affected by HIF. In conclusion, intravenous jugular vein injection of siRNA strongly targets the lung tumor and is effective in gene inhibition as demonstrated for HIF-1a and HIF-2a.

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

“…33 HIF-1a has been considered as an attractive molecular target for the development of novel cancer therapies. 34,35 Lentiviral vector has recently received considerable attention because it infects non-dividing cells and has a target gene integrated into the genome of target cells with long-term expression and less immune response. Therefore, in the present study, we explored therapeutic potential of lentivirus targeting HIF-1a in the treatment of TNBCs.…”

Comparison of the Effects of Carbon Ion and Photon Irradiation on the Angiogenic Response in Human Lung Adenocarcinoma Cells

“…RNA extraction and RT-PCR were performed as described previously (14). Cycling conditions were 50 C for 2 min and then 95 C for 10 min, followed by 45 cycles of 94 C for 10 sec, 54 C for 10 sec, and 72 C for 30 sec.…”

The Epithelial Cell and Lung Cancer: The Link between Chronic Obstructive Pulmonary Disease and Lung Cancer

“…VEGF correlates with progression, metastasis and poorer prognosis. Injection of siRNA against HIF-1α and HIF-2α was shown to reduce angiogenesis and prolong survival in a Lewis lung carcinoma model [83]. Bevacizumab, a targeted monoclonal antibody against VEGF, has shown to be effective in stage II and I trials in combination with standard chemotherapy and, thus, is now part of standard first-line treatment for stage IV NSCLC.…”