Abstract
Background: The arylidene indanone scaffold has contributed many lead molecules in chemotherapeutic anticancer agent research.
Objectives: To determine the oxidant-scavenging activities and antiproliferative activity of (2E)-2-benzylidene-4,7-dimethyl-2,3-dihydro-1H-inden-1-one (MLT-401), an arylidene indanone derivative.
Methods: Jurkat cells, primary lymphocytes, and Vero cells were treated with MLT-401. Antioxidant properties of MLT-401 were determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH)-based, 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS)-based, and ferric-reducing antioxidant potential (FRAP) assays. Inhibition of cell proliferation was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based assay. Nuclear status was determined using a DNA fragmentation assay, and cell cycle stage was analyzed by flow cytometry. Mitochondrial membrane enzyme activities were measured using colorimetric methods.
Results: The antioxidant assays gave MLT-401 half maximal inhibitory concentration (IC50) values of 1611 nM (DPPH-based assay), 2115 nM (ABTS-based assay), and 1586 nM (FRAP assay). MLT-401 inhibited proliferation of Jurkat cells with a concentration for 50% of maximal inhibition of cell proliferation (GI(50)) of 341.5 nM, being 12- and 9-fold less than GI(50) concentrations for normal lymphocytes and Vero cells, respectively. MLT-401 caused nuclear fragmentation and DNA laddering as seen by electrophoresis. Jurkat cells showed a time-dependent accumulation of sub G(0)/G(1) cells after MLT-401 treatment. Mitochondrial membrane-bound Na+/K+ ATPase, Ca2+ ATPase, and Mg2+ ATPase activities were inhibited by MLT-401 in a dose-dependent manner.
Conclusion: MLT-401 possesses significant antiproliferative activity and scavenges free radicals released through mitochondrial membrane damage in a Jurkat cell line model of cancer cells. Further investigation of MLT-401 as a chemotherapeutic anticancer agent and development of other arylidene indanone analogues are warranted. A detailed elucidation of mechanistic pathways is required for further development.