Temozolomide reduces the metastatic potential of Lewis lung carcinoma (3LL) in mice: role of alpha-6 integrin phosphorylation.

Abstract

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.

• Authors: L Tentori, C Leonetti, A Aquino
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 31A Issue 5 Pg. 746-54 ( 1995) ISSN: 0959-8049 [Print] England
• PMID: 7640049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Integrin alpha6
• Integrins
• Naphthalenes
• Dacarbazine
• Protein Kinase C
• calphostin C
• Tetradecanoylphorbol Acetate
• Temozolomide

Topics

• Animals
• Antineoplastic Agents
• Carcinoma, Lewis Lung (drug therapy, metabolism, secondary)
• Cell Adhesion (drug effects)
• Cell Membrane (enzymology)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Dose-Response Relationship, Drug
• Integrin alpha6
• Integrins (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Naphthalenes (therapeutic use)
• Phosphorylation
• Protein Kinase C (antagonists & inhibitors)
• Temozolomide
• Tetradecanoylphorbol Acetate (pharmacology)
• Tumor Cells, Cultured (drug effects)