Carbon chain length modulates MDA-MB-231 breast cancer cell killing mechanisms by mitochondrially targeted aryl-urea fatty acids.

Targeting the tumor cell mitochondrion could produce novel anti-cancer agents. We designed an aryl-urea fatty acid ( 1g ; 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid) that disrupted the mitochondrion and decreased MDA-MB-231 breast cancer cell viability. To optimize the aryl-ureas the present study evaluated mitochondrial targeting by 1g analogues containing alkyl chains between 10-17 carbons. Using the dye JC-1, the C12-C17 analogues efficiently disrupted the mitochondrial membrane potential (IC 50 s 3.5±1.2 to 7.6±1.1 µM) and impaired ATP production; shorter analogues were less active. 7-Aminoactinomycin D/annexin V staining and flow cytometry showed that these agents activated the killing mechanisms of necrosis and apoptosis to varying extents (7-aminoactinomycin D/annexin V staining ratios 4.3-6.0). Indeed, 1g and its C17 analogue preferentially activated necrosis and apoptosis, respectively (ratios 2.1 and 16). Taken together, alkyl chain length is a determinant of mitochondrial targeting by aryl-ureas and can be varied to develop analogues that activate apoptosis or necrosis in a regulated fashion.