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Mn‐SOD antisense upregulates in vivo apoptosis of squamous cell carcinoma cells by anticancer drugs and γ‐rays regulating expression of the BCL‐2 family proteins, COX‐2 and p21
Author(s) -
Ueta Eisaku,
Yoneda Kazunori,
Kimura Tsuyoshi,
Tatemoto Yukihiro,
Doi Sayoko,
Yamamoto Tetsuya,
Osaki Tokio
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1513
Subject(s) - apoptosis , transfection , in vivo , microbiology and biotechnology , biology , cell culture , cancer research , medicine , biochemistry , genetics
Abstract ROIs and their scavengers are associated with apoptosis induction by anticancer drugs and γ‐rays, but the details have not been clarified. We examined the effect of transfection of Mn‐SOD antisense on apoptosis by 5‐FU, PLM, CDDP and γ‐rays using nu/nu mice. After inoculation of Mn‐SOD antisense–transfected SCC cells into the subcutis of each mouse's back, they slowly multiplied to form tumors sized 1,460 ± 70 mm 3 at day 60, while control vector‐transfected SCC cells rapidly multiplied, with a mean tumor size of 2,330 ± 220 mm 3 . Inversely, mice in the Mn‐SOD antisense group survived longer (mean survival duration 94.4 ± 12.7 days) compared to those in the empty vector group (67.3 ± 6.8 days). After treatment with 5‐FU (5 μg/day), PLM (50 μg/day), CDDP (10 μg/day) and γ‐rays (2 Gy/day), mean survival times were largely prolonged, to 126.3 ± 22.7, 123.0 ± 22.1, 136.3 ± 24.0 and 143.0 ± 20.8 days, respectively, while mean survival times in the empty vector group were 91.7 ± 14.8, 85.7 ± 13.3, 97.5 ± 16.0 and 100.7 ± 17.1 days, respectively. Immunohistologically, tumors in the Mn‐SOD antisense group revealed additional nick end‐labeled cells compared to those in the empty vector group. In comparison, strong expression of Bax, Bak and p21 waf1/cip1 and suppressed expression of Bcl‐2, Bcl‐X L and COX‐2 were observed in the Mn‐SOD antisense group and the expression pattern of these proteins was the inverse in the empty vector group. The increased expression of these proapoptotic proteins appeared to be p53‐independent because p53 protein expression was not increased in the antisense group. These immunohistologic results were supported by Western blotting of each protein. In conclusion, Mn‐SOD antisense transfection is advantageous for apoptosis induction of SCC cells by anticancer drugs and γ‐rays through induction of proapoptotic Bcl‐2 family proteins and suppression of antiapoptotic protein expression. © 2001 Wiley‐Liss, Inc.