Relationship of cellular energy parameters to cytotoxicity for AG-17, lonidamine and cyclocreatine in four human tumor cell lines.

Abstract

The cytotoxicity and effect on cellular energy parameters of AG-17, lonidamine and cyclocreatine were examined in four human tumor cell lines: MCF-7 breast carcinoma, SW2 small cell lung carcinoma, A2058 melanoma and A2058-055, a subline of A2058 transfected with the creatine kinase gene. Although these cell lines had widely differing levels of creatine kinase activity, there were no differences in their sensitivity to cyclocreatine. The MCF-7 cells were most sensitive to AG-17 and to lonidamine with 90% cell killing by 50 mu M and 115 mu M of the drugs after 72 h exposure, respectively. The percent of coupled respiration in the cells was 60-70% in the absence of drug exposure and was decreased to 30-40% after 24 h of exposure to each of the drugs. Cytochrome C oxidase activity was decreased by 8- to 9-fold in the high creatine kinase expressing cell lines (SW2 and A2058-055) after exposure to AG-17 (250 mu M) for 24 h. Lonidamine (250 mu M) exposure decreased hexokinase activity in the cells to 30-40% of normal in 24 h. Extra-cellular lactate levels increased most markedly in the media of the MCF-7 and SW2 cells exposed to AG-17 (100 and 250 mu M) for 24 h. Although no specific enzymatic target was effected, cyclocreatine exposure resulted in a decrease in the ATP content of the cells, especially in the MCF-7 cells where ATP was decreased to 30% of normal upon 24 h exposure to the drug. These results provide a rationale for the use of these agents in combination with each other or in combination with cytotoxic anticancer therapies targeted on cellular DNA.

• Authors: G Ara, B Teicher
• Journal: International journal of oncology (Int J Oncol) Vol. 8 Issue 5 Pg. 865-73 (May 1996) ISSN: 1019-6439 [Print] Greece
• PMID: 21544439 (Publication Type: Journal Article)