Enhanced tumor radiosensitivity by a survivin dominant-negative mutant.
Radiosensitivity of tumors is due to a complex interaction of various factors, it has been reported that survivin also acts as a constitutive and inducible radioresistance factor in a panel of tumor cells and approaches designed to inhibit survivin expression or function may lead to tumor sensitisation to chemical and physical agents. Previously, we found that the plasmid encoding the phosphorylation-defective mouse survivin threonine 34-->alanine mutant complexed to DOTAP-chol liposome (Lip-mS) can suppress murine primary breast carcinoma. However, little is known regarding the biological effect of Lip-mS combined with radiation. The present study was designed to determine whether Lip-mS could enhance the anti-tumor activity of radiation. The Lewis Lung Carcinoma (LLC) cells treated with a combination of Lip-mS and radiation displayed apparently increased apoptosis compared with those treated with Lip-mS or radiation alone. Mice bearing LLC tumors were treated with intravenous injections of Lip-mS and radiation, the combined treatment significantly reduced mean tumor volume compared with either treatment alone. Moreover, the anti-tumor effect of Lip-mS combined with radiation was greater than their additive effect when compared with the expected effect of the combined treatment. These data suggest that inhibition of survivin using a dominant-negative mutant, survivin T34A, could sensitize LLC cells to radiation efficiently and the synergistic anti-tumor activity may in part result from increasing the apoptosis of tumor cells, inhibiting tumor angiogenesis and inducing a tumor-protective immune response in the combined treatment.
Yuan
Qing-Zhong
QZ
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, P.R. China.
Wang
Chun-Ting
CT
Mao
Yong-Qiu
YQ
Zhang
Peng
P
Shi
Hua-Shan
HS
Li
Zhi-Yong
ZY
Pan
Li
L
Yu
Dan-Dan
DD
Leng
Fei
F
Chen
Xiang
X
Ying
Wei
W
Xu
Jing-Hui
JH
Li
Wei
W
Wu
Fan
F
Wen
Yuan
Y
Ma
Tian-Tai
TT
Wei
Yu-Quan
YQ
D000818:Animals; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000532:radiotherapy*; D002784:Cholesterol / Q000494:pharmacology; D003131:Combined Modality Therapy / Q000379:methods; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005799:Genes, Dominant; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000502:physiology*; D010957:Plasmids; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011836:Radiation Tolerance / Q000235:genetics*; D011878:Radiotherapy / Q000379:methods; D012097:Repressor Proteins; D000077022:Survivin; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
C117749:Birc5 protein, mouse; D005229:Fatty Acids, Monounsaturated; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D008869:Microtubule-Associated Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000644:Quaternary Ammonium Compounds; D012097:Repressor Proteins; D000077022:Survivin; D013778:Tetrazolium Salts; D013844:Thiazoles; D002784:Cholesterol; C022616:thiazolyl blue; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane