We find that (i) many types of human adenocarcinoma cells take up more and retain longer the positively charged rhodamine 123 than that of normal epithelial cells; (ii) rhodamine 123 is specifically accumulated in mitochondria; (iii) rhodamine 123 is toxic to carcinoma cells but not normal epithelial cells; (iv) rhodamine 123 only reduces the clonogenic ability of carcinoma cells but not normal epithelial cells; (v) a significant prolonged survival in carcinoma-bearing mice by rhodamine 123 has been achieved; (vi) the efficacy of rhodamine 123 as a principal chemotherapeutic agent can be greatly enhanced by a combination therapy with 2-deoxyglucose, an inhibitor for glycolysis, which alone has no antitumor activity. Therefore, it seems justified to explore whether rhodamine 123 can be developed as an useful anticarcinoma drug. If it is not useful as a pricipal drug, it may find use in adjuvant therapy since mitochondria appear to be the primary target and none of the established anticancer drugs is known to exert toxicity through mitochondria. If none of these goals is attained, our studies with rhodamine 123 may lead to better understanding of mitochondria in human carcinoma cells.
Specific aims are (a) to characterize the molecular basis for rhodamine 123 toxicity; (b) to characterize the cellular basis for prolonged retention of rhodamine 123 in human adenocarcinoma cells and (c) to increase the efficacy of anticarcinoma activity of rhodamine 123 in animals by a combination therapy with various inhibitors of glucose, glutamine and cholesterol metabolism as well as drugs perturbing cytoskeleton and calmodulin.
