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The new platinum(IV) derivative LA-12 shows stronger inhibitory effect on Hsp90 function compared to cisplatin

DOI: 10.1186/1476-4598-9-147

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Abstract:

LA-12 disrupts cellular proliferation regardless of the p53 status in the cells, however the potency of the drug is greatly enhanced by the presence of a functional p53, indicating several mechanisms of action. Similarly to cisplatin, an interaction of LA-12 with molecular chaperone Hsp90 was proposed. Binding of LA-12 to Hsp90 was demonstrated by Hsp90 immunoprecipitation followed by platinum measurement using atomic absorption spectrometry (AAS). An inhibitory effect of LA-12 on Hsp90 chaperoning function was shown by decrease of Hsp90-assisted wild-type p53 binding to p21WAF1 promoter sequence in vitro and by accelerated ubiqutination and degradation of primarily unfolded mutant p53 proteins in cells exposed to LA-12.To generalize our findings, LA-12 induced degradation of other Hsp90 client proteins such as Cyclin D1 and estrogen receptor was shown and proved as more efficient in comparison with cisplatin. This newly characterised molecular mechanism of action opens opportunities to design new cancer treatment strategy profitable from unique LA-12 properties, which combine DNA damaging and Hsp90 inhibitory effects.Cisplatin [cis-diamminedichloroplatinum(II)] is a platinum-based anticancer drug commonly used for treatment of different types of cancer, including ovarian, testicular, head and neck or lung carcinomas [1]. Although cisplatin exerts significant anti-tumour activity, cisplatin-based therapies cause numerous side effects, such as nephrotoxicity, neurotoxicity and nausea. The intrinsic as well as acquired resistances to cisplatin-based therapy also represent substantial complications for the treatment of tumours.For this reason, vast efforts were committed to develop novel platinum-based complexes to overcome platinum resistance, to reduce cisplatin side effects and to introduce novel mechanisms of anti-cancer action. Two derivatives, carboplatin (cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II)) and oxaliplatin (trans-R,R.cyclohexane-1,2-diammine

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