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Current Cancer Drug Targets
ISSN (Print): 1568-0096
ISSN (Online): 1873-5576
VOLUME: 14
ISSUE: 2
DOI: 10.2174/1568009614666140113115651      Price:  $58









Cationic Liposome Mediated Delivery of FUS1 and hIL-12 Coexpression Plasmid Demonstrates Enhanced Activity against Human Lung Cancer

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Author(s): Jiang Ren, Chuanjiang Yu, Shifei Wu, Feng Peng, Qianqian Jiang, Xuechao Zhang, Guoxing Zhong, Huashan Shi, Xiang Chen, Xiaolan Su, Xinmei Luo, Wen Zhu and Yuquan Wei
Pages 167-180 (14)
Abstract:
FUS1 is one of the most important tumor suppressor genes in lung cancer, as well as an important immunomodulatory molecule. Interleukin (IL)-12 has attracted considerable interest as a potential anti-tumor cytokine. Cationic liposome has been shown to effectively deliver therapeutic genes to the lungs and control metastatic lung tumors when administered intravenously. Here we evaluated the enhanced efficacy of cationic liposome-mediated delivery of FUS1 and human IL (hIL)-12 eukaryotic coexpression plasmid (pVITRO2-FUS1-hIL-12) against the human lung cancer in HuPBL-NOD/SCID mice model by local and systemic administration, and explored the related molecular mechanism. Our study demonstrated that FUS1-hIL-12 coexpression could more sufficiently inhibit tumor growth and experimental lung metastasis, significantly prolong the survival of experimental lung metastasis mice. Moreover, FUS1-hIL-12 coexpression performed higher antitumor activity and lower toxicity in the inhibition of experimental lung metastatic tumor compared to cisplatin. We further identified that FUS1-hIL-12 coexpression could induce strong antitumor immune response by secreting much higher levels of human interferon-γ (hIFN-γ) and hIL-15, enhancing expression of MHC- and Fas, increasing infiltration of activated human CD4+ and CD8+ T lymphocytes. FUS1-hIL-12 coexpression could also obviously induce tumor cell apoptosis and inhibit tumor cell proliferation partly by higher activation of STAT1 signal pathway and upregulation of p53. In addition, FUS1-hIL-12 coexpression also superiorly reduced the angiogenesis in tumors, which might be associated with downregulation of VEGF and VEGFR, and upregulation of human IP-10. Our results therefore suggest that cationic liposome-mediated FUS1-hIL-12 coexpression may be a new promising strategy for lung cancer treatment in clinical studies.
Keywords:
Cationic liposome, FUS1-hIL-12 eukaryotic coexpression, Gene therapy, HuPBL-NOD/SCID, Lung cancer, Molecular mechanism.
Affiliation:
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Keyuan 4th Road, NO. 1, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, P. R. China.