CISPLATIN AFFECTS TESTICULAR STEROIDOGENESIS TRHOUGH A MECHANISM THAT INVOLVES ROS-MEDIATED P450SCC INHIBITION

SUÁREZ GV; GARCÍA MMMS; ACQUIER A; BRION L; GOROSTIZAGA AB; GÓMEZ N; MÉNDEZ CF; PAZ C

Río de Janeiro, Brasil

Congreso; 13th International Congress of Endocrinology; 2008

International Society of Endocrinology

Platinum compounds (PtC) such as carboplatin (Cp), oxaliplatin (Ox) and cisplatin (Cs) are widely used in the treatment of different cancers, including testicular tumours. The different PtC affect steroidogenesis in varying degrees, however, the underlying mechanism is not fully established. The aim of this work was to analyze the in vitro toxicity of PtC on testicular steroidogenesis and the involved mechanism. Mouse interstitial testicular cells were exposed to (5h) Cp, Ox or Cs (50ƒÊM), under basal conditions (C) or after stimulation with hCG or 8Br-cAMP and testosterone (T) production was quantified by RIA. Cs significantly inhibited (p<0.05) T production (ng/ml) in basal (C = 9.0±2.8; C+Cs = 5.1±1.6) and stimulated conditions (hCG = 150.3±23.3; cAMP = 126.9±35.4; hCG+Cs = 106.6±22.0; cAMP+Cs = 71.0±15.0), while Cp and Ox had no effect. The site of action of Cs on T production was studied using different steroidogenic substrates: 22R-hydroxycholesterol (22R), a freely diffusible cholesterol analogue, and pregnenolone (P5) as P450scc and 3beta-Hydroxysteroid dehydrogenase substrates respectively. Cs significantly inhibited (p<0.05) 22R-supported T production (22R = 32.0±4.1; 22R+Cis = 15.5±3.1) while it produced a non-significant inhibition of P5-supported T synthesis. A ROS-generating compound, ABAP, also inhibited 22R-supported T synthesis (22R+ABAP = 12.4±4.1) and an analogue of alpha-tocopherol, Trolox (Tx), abrogated this effect (p<0.05). Moreover, Tx blocked also Cs effect on 22R-supported T production (22R+Cs+Tx = 34.0±3.3; 22R+Tx = 29.7±3.4). Similar results were obtained when the effect of PtC on steroidogenesis was studied on MA-10 Leydig cells. Long term exposure of MA-10 cells to PtC inhibited cell proliferation and induced apoptosis in a magnitude comparable to the steroidogenic effect. MAP kinase/ MAPK phosphatase pathways are also activated by Cs. However, the effect was detected after long term exposure to the drug, suggesting an indirect action of Cs on that pathway. Our results show that Cs exerts a citotoxic effect on testicular steroid synthesis through ROS generation and inhibition of P450scc enzymatic activity. The activation of MAP kinases after prolonged Cs treatment might be due, at least in part, to Cs-induced ROS generation.