Temozolomide reduces the metastatic potential of Lewis lung carcinoma (3LL) in mice: role of alpha-6 integrin phosphorylation.
The involvement of protein kinase c (PKC) in the mechanism underlying the antimetastatic properties of triazenes was studied in C57BL/6 mice bearing Lewis lung carcinoma (3LL). In vivo and in vitro treatment with temozolomide, an in-vitro active analogue of dacarbazine, or calphostin c produced a concentration-dependent reduction of spontaneous and artificial metastases. Both agents reduced the ability of 3LL cells to adhere to endothelium. Diethylaminoethyl (DEAE)-sepharose chromatography of cell extracts revealed that incubation of 3LL cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) caused a rapid translocation of protein kinase c activity from cytosol to the membrane fraction. Membrane PKC activity induced by TPA was reduced by 60% after treatment with temozolomide. Coincident with these changes, TPA induced phosphorylation of alpha-6 integrin, whereas temozolomide or calphostin c abolished the appearance of this phosphoprotein. These results suggest that temozolomide reduced metastatic potential by interfering with alpha-6 phosphorylation induced by PKC activation.
Tentori
L
L
University of Rome Tor Vergata, Italy.
Leonetti
C
C
Aquino
A
A
D000818:Animals; D000970:Antineoplastic Agents; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D039503:Integrin alpha6; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000627:therapeutic use; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D039503:Integrin alpha6; D016023:Integrins; D009281:Naphthalenes; D003606:Dacarbazine; D011493:Protein Kinase C; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate; D000077204:Temozolomide