Premium
Carbon Chain Length Modulates MDA‐MB‐231 Breast Cancer Cell Killing Mechanisms by Mitochondrially Targeted Aryl−Urea Fatty Acids
Author(s) -
Murray Michael,
Roseblade Ariane,
Chen Yongjuan,
Bourget Kirsi,
Rawling Tristan
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900577
Subject(s) - apoptosis , annexin , mitochondrion , viability assay , necrosis , flow cytometry , cancer cell , programmed cell death , biology , cell , biochemistry , chemistry , microbiology and biotechnology , cancer , genetics
Targeting the tumor cell mitochondrion could produce novel anticancer agents. We designed an aryl−urea fatty acid ( 1 g ; 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 1 g 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, 1 g 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.