RESUMO
Studies suggest that oxalate is involved in the development oxaliplatin-induced peripheral sensory neuropathy (OPSN). This study aimed to compare the neurotoxic effects of oxaliplatin with its oxalate-free cytotoxic analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice. Oxaliplatin and LLC-1402 were intravenously injected in male Swiss mice with a total of nine injections. Oxalate was intraperitoneally injected in other animals. The development of OPSN was evaluated using mechanical and thermal sensitivity tests. Dorsal root ganglia of the mice were removed to evaluate c-Fos, ATF3 and iNOS expression and a sample of blood was collected for leukocyte count and hepatic and renal biochemical function tests. Oxaliplatin and LLC-1402 decreased the mechanical and thermal nociceptive threshold, whilst oxalate lead to a partial and later increase in the mechanical sensitivity (P<0.05). c-Fos, ATF3 and iNOS expressions were increased in neuronal cells during and after the end of the injections in animals treated with oxaliplatin and LLC-1402 (P<0.05), even though oxaliplatin lead to an earlier increase. Only c-Fos expression was elevated during the period of injections in the oxalate group (P<0.05), but this expression reduced after the end of the treatment. c-Fos expression was also shown in glial satellite cells only in the oxaliplatin-treated animals. Oxaliplatin and LLC-1402 reduced leukocyte count (P<0.05), but did not change renal and liver functions. In conclusion, oxalate may contribute to an earlier development of peripheral sensory neuropathy. However, the antitumor cytotoxic mechanism of oxaliplatin seems to be the main responsible by its neurotoxic effect.
Assuntos
Antineoplásicos/toxicidade , Compostos Organoplatínicos/toxicidade , Oxalatos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Antineoplásicos/química , Masculino , Camundongos , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Compostos Organoplatínicos/química , Oxaliplatina , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologiaRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger α-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or α-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress by-products in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists.
Assuntos
Antineoplásicos/toxicidade , Doenças do Sistema Nervoso Periférico/prevenção & controle , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Acetanilidas/farmacologia , Animais , Ácidos Borônicos/toxicidade , Bortezomib , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Purinas/farmacologia , Pirazinas/toxicidade , Canal de Cátion TRPA1 , Ácido Tióctico/farmacologia , Canais de Potencial de Receptor Transitório/análise , Canais de Potencial de Receptor Transitório/fisiologiaRESUMO
This work describes the synthesis and characterization of three novel complexes derived from N-benzyl-ethylenediamine and oxalate. Precursor compounds were synthesized by reacting N-benzyl-ethylenediamine with K(2)PtCl(4). Subsequent substitution of chlorides by oxalate led to the final products. Elemental analysis and the infrared, (1)H, (13)C, and (195)Pt NMR spectra of these complexes were provided. The cytotoxic activities were investigated against human non-small cell lung carcinoma (A(549)), mouse non-metastatic cell skin melanoma (B16-F1), mouse metastatic cell skin melanoma (B16-F10), human cell breast adenocarcinoma (MDA-MB-231) and normal cell lines such as baby hamster cell kidney (BHK-21), hamster cell ovary (CHO) and compared to cisplatin and carboplatin under the same experimental conditions. The presence of oxalate as a leaving group conferred an interesting cytotoxicity profile to the complexes in the tested cell lines.
Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Etilenodiaminas/química , Compostos Organoplatínicos/síntese química , Oxalatos/química , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Células CHO , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cricetinae , Cricetulus , Humanos , Camundongos , Compostos Organoplatínicos/química , Compostos Organoplatínicos/toxicidadeRESUMO
BACKGROUND: Enhanced removal of cisplatin-DNA adducts has been reported as one of main causes of cell resistance to cisplatin. This particular resistance mechanism may be circumvented by platinum complexes that bind differently to DNA. One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts. METHODS: We synthesised new trans platinum complexes, trans-[PtCl2(cyclohexylamine)(dimethylamine)] and trans-[PtCl2(OH)2(cyclohexylamine)(dimethylamine)], previously evaluated as cytotoxic agents towards different cancer and normal cell lines. These trans platinum compounds were highly effective against a panel of tumoral cell lines either sensitive to or with acquired resistance to cisplatin. RESULTS: In the present work we examined the mechanisms induced by these compounds to cause tumour cells toxicity. We have found that these compounds induced a complete blockade at the S phase of the cell cycle inhibiting total mRNA transcription and precluding p53 activation. CONCLUSION: In contrast to other DNA-damaging agents, these compounds do not induce senescence-associated permanent arrest. Furthermore, only a small percentage of these cells enter into apoptosis, with most of the population dying by a necrosis-like mechanism.
Assuntos
Antineoplásicos/farmacologia , DNA/biossíntese , Compostos Organometálicos/farmacologia , Compostos Organoplatínicos/farmacologia , Transcrição Gênica/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Senescência Celular , Relação Dose-Resposta a Droga , Humanos , Ligantes , Necrose , Compostos Organometálicos/síntese química , Compostos Organometálicos/toxicidade , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/toxicidade , RNA Mensageiro/metabolismoRESUMO
This work describes the synthesis and characterization of six new dinuclear platinum complexes having N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines and N-benzyl-1,6-hexanediamines as ligands. They were prepared by the reaction of cis-[PtCl(2)(DMSO)(2)] (DMSO=dimethyl sulfoxide) with the appropriate ligand in water, except for one of them, which was prepared from K(2)PtCl(4). We also report the cytotoxic activity and cellular accumulation of three of these complexes in a human small-cell lung carcinoma cell line and its resistant subline. Resistant cells exhibited a lesser degree of cross-resistance to these compounds when compared to cisplatin. The accumulation of platinum in both cell lines followed the same pattern, i.e. approximately the same intracellular platinum concentration yielded the same cytotoxic effect independent of the nature of the platinum complex used.