Toxicity Of Platinum Drugs Research Articles

Biologiczne podstawy terapii przeciwnowotworowej z zastosowaniem leków platynowych. Oddziaływanie z cytochromem c

Przeciwnowotworowe leki platynowe są szeroko stosowane w praktyce klinicznej w terapii wielu nowotworów, jednakże skutki uboczne terapii z ich udziałem, m. in. zależna od dawki nefrotoksyczność oraz oporność komórek nowotworowych, limitują ich użycie. Cytochrom c jest małą hemoproteiną pełniącą funkcję transportera elektronów, ulokowaną w mitochondriach, która odgrywa również istotną rolę w procesie apoptozy komórki. Platynowanie specyficznych łańcuchów bocznych, które wpływa na biologiczne funkcje białek i enzymów poprzez tworzenie mocnych wiązań koordynacyjnych, może mieć wpływ na ogólny mechanizm aktywności i toksyczność leków platynowych. W celu zrozumienia natury tych oddziaływań przeanalizowane zostały oddziaływania cisplatyny i jej pochodnych z sygnałowym białkiem apoptozy — cytochromem c.

Abstract 4389: Copper and platinum uptake in cultured rat dorsal root ganglion neurons

Abstract Peripheral neuropathy is a dose-limiting toxicity of platinum drugs due to their accumulation in the dorsal root ganglia (DRG) and damage to sensory neurons. Our previous studies showed a specific pattern of expression of copper transporters in rat DRG tissue (Liu JJ et al 2009; Ip V et al 2010). Here we aimed to investigate their functional activity in the uptake of copper and platinum in cultured DRG neurons in vitro. Dissociated rat DRG neurons were cultured in N2-supplemented Neurobasal-A medium. Cellular metal levels were measured by the inductively coupled plasma mass spectrometry. The copper content of the cultured DRG neurons increased linearly with time (R2, 0.7952 ∼ 0.8903) during a one hour exposure to 3 ∼ 100 µM of CuCl2. The rate of cellular uptake of copper had nonlinear dependence (R2, 0.9629) on the exposure concentration of CuCl2, with a maximal uptake rate of 0.237 ± 0.041 nmole/min/mg protein and CuCl2 concentration achieving half-maximal uptake of 49.1 µM. The uptake of copper was temperature-dependent, stimulated by ascorbate and inhibited by zinc. CTR1 mRNA was detectable in cultured DRG neurons and its protein co-localised with microtubule-associated protein 2-positive neuronal cell bodies. Oxaliplatin inhibited copper uptake by DRG neurons and their platinum content increased linearly with time (R2, 0.916) during a one hour oxaliplatin exposure. In conclusion, CTR1 is functionally expressed by rat DRG neurons in primary culture. Oxaliplatin accumulates and inhibits copper uptake in DRG neurons. Supported by research grants from Cancer Society of New Zealand and McBeath Child Cancer Trust Fund. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4389. doi:10.1158/1538-7445.AM2011-4389

Fast cleavage of a diselenide induced by a platinum(II)–methionine complex and its biological implications

Platinum-based anticancer drugs such as cisplatin induce increased oxidative stress and oxidative damage of DNA and other cellular components, while selenium plays an important role in the antioxidant defense system. In this study, the interaction between a platinum(II) methionine (Met) complex [Pt(Met)Cl 2] and a diselenide compound selenocystine [(Sec) 2] was studied by electrospray ionization mass spectrometry, high performance liquid chromatography mass spectrometry, and 1H NMR spectroscopy. The results demonstrate that the diselenide bond in (Sec) 2 can readily and quickly be cleaved by the platinum complex. Formation of the selenocysteine (Sec) bridged dinuclear complex [Pt 2(Met- S,N) 2(μ-Sec- Se,Cl)] 3+ and Sec chelated species [Pt(Met- S,N)(Sec- Se,N)] 2+ was identified at neutral and acidic media, which seems to result from the intermediate [Pt(Met- S,N)(Sec- Se)Cl] +. An accelerated formation of S–Se and S–S bonds was also observed when (Sec) 2 reacted with excessive glutathione in the presence of [Pt(Met)Cl 2]. These results imply that the mechanism of activity and toxicity of platinum drugs may be related to their fast reaction with seleno-containing biomolecules, and the chemoprotective property of selenium agents against cisplatin-induced toxicity could also be connected with such reactions.