Trans-platinum(II) complexes with cyclohexylamine as expectator ligand induce necrosis in tumour cells by inhibiting DNA synthesis and RNA transcription.

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.

Trans-platinum(II) complexes with cyclohexylamine as expectator ligand induce necrosis in tumour cells by inhibiting DNA synthesis and RNA transcription

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 (AU)

Preparation and characterization of novel trans-[PtCl(2)(amine)(isopropylamine)] compounds: cytotoxic activity and apoptosis induction in ras-transformed cells.

The synthesis and chemical characterization of three new transplatinum complexes of structural formula trans-[PtCl(2)(amine)(isopropylamine)] (amine = n,n-dimethylamine, propylamine, and butylamine), 1-3, are described. Cytotoxicity tests in tumor cell lines sensitive to cis-DDP (Jurkat, Hela, and Vero) and also in tumor cell lines overexpressing ras oncogenes and resistant to cis-DDP (HL-60 and Pam 212-ras) show that complexes 1 and 3 have higher cytotoxic activity than cisplatin. Moreover, these two trans-Pt(II) complexes kill Pam 212-ras cells through apoptosis induction. These results suggest that trans-PtCl(2) complexes with asymmetric aliphatic amines may be considered a new class of biologically active trans-platinum drugs.