Apoptosis-promoting gene (bax) transfer potentiates sensitivity of squamous cell carcinoma to cisplatin in vitro and in vivo.
Modulation of apoptosis may potentiate the sensitivity of tumor cells to chemotherapeutic agents, thus improving the clinical outcome of cancer treatment. Bax, an apoptosis-promoting member of the bcl-2 family, may be a key factor influencing the chemosensitivity of tumor cells, however, its involvement in cellular sensitivity to anti-cancer drugs remains uncertain in squamous cell carcinoma (SCC). To investigate the role of bax gene expression in modulating cisplatin (CDDP)-induced apoptosis in vitro, an established CDDP-resistant human head and neck SCC (IMC-3 cell line) was transfected with bax gene-bearing mammalian expression vector. Overexpression of the bax gene in CDDP-resistant IMC-3 cells elevated the CDDP susceptibility of tumor cells to a level similar to that of the parental IMC-3 cells. In an in vivo study, percutaneous transfer of apoptosis-promoting bax gene by particle-mediated (gene gun) delivery caused overexpression of Bax in SCC, which was confirmed by immunohistochemical staining, and inhibited the growth of mouse CDDP-resistant SCC. Furthermore, combination therapy with bax gene transfer and subcutaneous administration of CDDP at 3-day intervals markedly inhibited the growth of mouse SCC. Thus, overexpression of bax in SCC by a gene gun system appears to be a rational approach to improving the efficacy of chemotherapy and treatment outcome. We suggest that exogenous bax expression may have therapeutic applications for enhancing chemotherapy in SCC.
Sugimoto
C
C
Department of Otorhinolaryngology, Fukui Medical University, Fukui, Japan.
Fujieda
S
S
Seki
M
M
Sunaga
H
H
Fan
G K
GK
Tsuzuki
H
H
Borner
C
C
Saito
H
H
Matsukawa
S
S
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000627:therapeutic use* / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006801:Humans; D008441:Maxillary Neoplasms; D051379:Mice; D008809:Mice, Inbred C3H; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D002945:Cisplatin