ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , DNA/biosynthesis , Organometallic Compounds/pharmacology , Organoplatinum Compounds/pharmacology , Transcription, Genetic/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Apoptosis , Cell Cycle , Cell Line, Tumor , Cellular Senescence , Dose-Response Relationship, Drug , Humans , Ligands , Necrosis , Organometallic Compounds/chemical synthesis , Organometallic Compounds/toxicity , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/toxicity , RNA, Messenger/metabolismABSTRACT
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)
Subject(s)
Humans , Male , Female , Antineoplastic Agents/pharmacology , DNA/biosynthesis , Antineoplastic Agents/chemical synthesis , Organometallic Compounds/pharmacology , Transcription, Genetic , Antineoplastic Agents/toxicity , Apoptosis , Cellular Senescence , Cell Cycle , Cell Line, Tumor , Necrosis , Organometallic Compounds/chemical synthesis , Organometallic Compounds/toxicity , RNA, Messenger/metabolism , LigandsABSTRACT
Programmed cell death or apoptosis is a mechanism for the elimination of cells that occurs not only in physiological processes but also in drug-induced tumor cell death. Thus, because cisplatin, cis-diamminechloroplatinum (II), produces important damages on the DNA inducing apoptosis in several cell lines it has become a widely used antitumor drug. However, cisplatin possesses some dose-limiting toxicities mainly nephrotoxicity. Pt(IV) complexes, such as iproplatin, ormaplatin, and JM216 are a new class of platinum complexes that exhibits less toxicity than cisplatin. Some of these complexes have shown significant antitumor activity and a low cross-resistance to cisplatin. In the present paper, we have analyzed the DNA binding mode and the cytotoxicity of a novel Pt(IV)-bis (monoglutarate) complex. The data show that this novel complex produces DNA interstrand cross-links to a higher extent and with a faster kinetics than cisplatin. Also the Pt(IV)-bis (monoglutarate) complex kills glioma cells at drug concentrations significantly lower than those of cisplatin. Interestingly, this Pt(IV) complex produces in the glioma cells characteristic features of apoptosis such as 'DNA laddering' and fragmented nuclei. Moreover, the p53 protein accumulates early in glioma cells as a result of Pt(IV)-bis (monoglutarate) treatment. These data indicate that the Pt(IV)-bis (monoglutarate) complex induces apoptosis in glioma cells through a p53-dependent pathway.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , DNA, Neoplasm/drug effects , Glioma/drug therapy , Glutarates/pharmacology , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Blotting, Western , Cell Survival/drug effects , Cross-Linking Reagents/metabolism , DNA, Neoplasm/metabolism , Electrophoresis, Polyacrylamide Gel , Glioma/genetics , Glioma/metabolism , Glutarates/chemical synthesis , Glutarates/metabolism , Humans , Magnetic Resonance Spectroscopy , Organoplatinum Compounds/chemical synthesis , Tumor Cells, Cultured , Tumor Suppressor Protein p53/biosynthesisABSTRACT
Hitherto, it has been generally accepted as a paradigm of the biochemical pharmacology of platinum antitumor drugs that a cis configuration of the leaving groups is necessary for antitumor activity of platinum compounds. However, it has been recently observed that certain trans-platinum complexes have both in vitro and in vivo antitumor activity. We previously reported the synthesis, characterization and cytotoxic activity against ras-transformed cells of several trans-[PtCl2LL'] complexes where L and L' are asymmetric aliphatic amines (L = dimethylamine and butylamine, L' = isopropylamine). The results reported in this paper show that the compounds trans-[PtCl2(isopropylamine)(dimethylamine)] and trans-[PtCl2(isopropylamine)(butylamine)] kill Pam 212-ras cisplatin resistant cells through apoptosis induction. Moreover, Western blot data show that both compounds inhibit overexpression of H-ras oncogene in Pam 212-ras cells. Altogether, these data indicate that, in contrast with cis-DDP, the apoptotic activity of these novel trans-Pt(II) compounds in ras-transformed cells is associated with their ability to abolish ras-overexpression.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Genes, ras/drug effects , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/genetics , Cell Line, Transformed/drug effects , Cells, Cultured , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic/drug effects , Keratinocytes/drug effects , Keratinocytes/pathology , Mice , Oncogene Protein p21(ras)/drug effects , Oncogene Protein p21(ras)/genetics , Organoplatinum Compounds/chemistryABSTRACT
In the present paper we present data on the synthesis, crystal structure and biological activity of bis(dipyridamole) tetrachloroplatinate(II).dipyridamole.dihydrate, [dpmH]2 PtCl4.dpm.2H2O. The crystals are Triclinic P1 with a = 11.490(2) A, b = 13.630(2) A, c = 15.81(1) A, a = 100.97(2) degrees, beta = 100.89(3) degrees, gamma = 112.35(1) degrees, Z = 1, M = 1885.9, Dx = 1.46 g/cm3, MoK alpha (lambda = 0.71069 A), mu = 0.0184 mm-1, R = 4.4%, Rw = 5.0%, 3231 (1 > 2 sigma (I)). The structure is stabilized by a hydrogen-bonding network. It was observed that although dpm alone is not able to alter the electrophoretic mobility of pUC8 DNA forms, the synthesized Pt-dpm compound substantially modifies the DNA conformation since it significantly alters the electrophoretic mobility of nicked and closed circular forms of pUC8 DNA. However, the alteration in mobility of pUC8 DNA induced by this compound upon binding is lower than that induced by cis-DDP. The analysis of the antiproliferative activity of the Pt-dpm salt against MDA-MB 468 (breast carcinoma) and HL-60 (leukemia) human cancer cells showed that this compound has ID50 values of 0.87 microM and 0.65 microM, respectively. Interestingly, it was found out that although the dpm molecule does not present any significant antiproliferative activity, the ID50 values of Pt-dpm are about 3-fold and 7-fold lower than those of cis-DDP and K2PtCl4, respectively. Altogether the biological data suggest that in Pt-dpm a synergic effect between cation and anion is produced.