The cytotoxicity of
platinum(II) complexes coordinated to a chiral
diamine, 1S,2S-diaminocyclohexane or
1R,2R-diaminocyclohexane and
1,10-phenanthroline or
3,4,7,8-tetramethyl-1,10-phenanthroline has been investigated in the renal proximal tubule HK-2 cell line. All
platinum(II) complexes exhibited lower cytotoxicity in HK-2 cells (IC50 1.7-25μM) than in A2780
ovarian cancer cells or
cisplatin-resistant A2780cisR cells (IC50 0.2-2.1μM) (at 48h). PHENSS ([Pt(1,10-
phenanthroline)(1S,2S-
dach)]2+) induced apoptosis and
necrosis in
ovarian cancer cells at concentrations that are relatively
cytostatic to renal cells.
Cisplatin was similarly or more cytotoxic to renal cells than
ovarian cancer cells. Similar trends were reflected with shorter term exposure (1.5h). PHENSS demonstrated a comparatively
cytostatic mode of action in renal cell cultures than
cisplatin, as demonstrated by lower toxicity at higher concentrations (90μM). PHENSS induced an elongated renal cell morphology, cytoskeletal stress fibre thickening, and increased β-
galactosidase activity, but no detectable change in
reactive oxygen species generation or cell cycle distribution. In contrast,
cisplatin treatment was associated with increased oxidative stress, cellular enlargement, G2/M arrest and apoptosis. The cytotoxicity of all
platinum(II) complexes in both renal and ovarian cell lines were reduced in the presence of organic
cation transporter (OCT) inhibitors
cimetidine,
disopyramide and
amantadine. PHENSS and analogues demonstrated low level genotoxicity in an in vitro micronuclei assay compared to
cisplatin or
etoposide. These findings highlight PHENSS and other phen-based unconventional
platinum(II) complexes as promising
anticancer agents with alternative modes of action that induce lower kidney cell toxicity and genotoxicity, while demonstrating greater
cisplatin-resistant
ovarian cancer cell toxicity.