Potentiation of the antimitochondrial and antiproliferative effects of bis(guanylhydrazones) by phenethylbiguanide.
The ability of methylglyoxal-bis(guanylhydrazone) (MGBG) and 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) to interact with the hypoglycemic agent, phenethylbiguanide (DBI), in affecting the bioenergetic functions of isolated rat liver mitochondria was studied. DBI was found to increase markedly the inhibitory effect of either 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) or MGBG on respiration of isolated rat liver mitochondria. Conversely, these bis(guanylhydrazones) enhanced the inhibitory potency of DBI and increased the apparent affinity of mitochondria for the drug. As with MGBG and 4,4'-diacetyldiphenylurea-bis(guanylhydrazone), the potassium cationophore, valinomycin, increased the sensitivity of mitochondrial respiration to DBI. It is suggested that the enhancement of bis(guanylhydrazone) inhibition of mitochondrial respiration by DBI involves inhibition of proton fluxes across the inner mitochondrial membrane and the subsequent alkalinization of the mitochondrial matrix. This drug interaction was extended to the level of antiproliferative activity in which DBI was found to potentiate the growth-inhibitory effects of MGBG on murine L1210 leukemia in vivo.
D000818:Animals; D002224:Carbanilides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006146:Guanidines / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000188:drug therapy*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008935:Mitoguazone / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010629:Phenformin / Q000494:pharmacology*; D011073:Polyamines / Q000494:pharmacology; D051381:Rats; D014634:Valinomycin / Q000494:pharmacology
D002224:Carbanilides; D006146:Guanidines; D011073:Polyamines; C100261:diacetyldiphenylurea bisguanylhydrazone; D014634:Valinomycin; D010629:Phenformin; D008935:Mitoguazone