RESUMO
The limiting factor for the use of Cisplatin in the treatment of different type of cancers is its toxicity and more specifically urogenital toxicity. Oxidative stress is a well-known phenomenon associated with Cisplatin toxicity. However, in Cisplatin treated group, abnormal animal behavior, decreased body weight, cellular and sub-cellular changes in the kidney and sperm abnormality were observed. Our investigation revealed that Cisplatin when administered in combination with a natural product derivative (Urs-12-ene-3α,24ß-diol, labeled as IN0523) resulted in significant restoration of body weight and protection against the pathological alteration caused by Cisplatin to kidney and testis. Sperm count and motility were significantly restored near to normal. Cisplatin caused depletion of defense system i.e. glutathione peroxidase, catalase and superoxide dismutase, which were restored close to normal by treatment of IN0523. Reduction in excessive lipid peroxidation induced by Cisplatin was also found by treatment with IN0523. The result suggests that IN0523 is a potential candidate for ameliorating Cisplatin induced toxicity in the kidney and testes at a dose of 100mg/kg p.o. via inhibiting the oxidative stress/redox status imbalance and may be improving the efflux mechanism.
Assuntos
Cisplatino/toxicidade , Rim/efeitos dos fármacos , Extratos Vegetais/farmacologia , Testículo/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antineoplásicos/toxicidade , Boswellia , Cristalografia por Raios X , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Distribuição Aleatória , Contagem de Espermatozoides/métodos , Motilidade dos Espermatozoides/efeitos dos fármacos , Motilidade dos Espermatozoides/fisiologia , Testículo/metabolismo , Testículo/patologia , Triterpenos/isolamento & purificaçãoRESUMO
In the present study, novel spiro derivatives of α-santonin were prepared and tested for their anticancer activity against a panel of six human cancer cell lines. Spiro-isoxazoline and spiro-isoxazolidine derivatives have been generated on C-ring of α-santonin (α-methylene-γ-butyrolactone) by the 1,3-dipolar cycloaddition of α-santonin derivative 6 with nitrile oxides 7 and nitrones 9 respectively. Among all, compound 10bâ³ had shown IC50 of 0.01, 0.5 and 0.3 µM against PC-3, THP-1 and MCF-7 cell lines respectively. Further, flow cytometry studies showed that PC-3 cells treated with the spiro-isoxazolidine derivative 10bâ³ were arrested in the sub G1 phase of the cell cycle in a concentration dependent manner. The spiro-isoxazolidine derivative 10bâ³ also showed concentration dependent inhibitory activity against NF-κB, p65 with 57% inhibition in 24 h at 10 µM.