Cytotoxicity, DNA strand breakage and DNA–protein crosslinking by a novel transplatinum compound in human A2780 ovarian and MCF-7 breast carcinoma cells

Farrell, Nicholas; Povirk, Lawrence F.; Dange, Yojana; DeMasters, Gerald; Gupta, Mona; Kohlhagen, Glenda; Khan, Qasim; Pommier, ﻿Yves; Gewirtz, David A.

doi:10.1016/j.bcp.2004.05.023

Cited by 53 publications

(30 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lack of pharmacological activity of transplatin was explained on the basis of these points; transplatin, due to steric reason, is unable to form 1,2-intrastrand cross-links between two adjacent purines in the same DNA strand (it mainly forms 1,3-interstrand cross-links) [8]. However, the transplatin analogues with planar amines exhibit cytotoxicity equivalent to cisplatin probably due to formation of DNA -protein cross-links [65] Ternary DNA -Pt -Protein cross-links (DPCLs) have also been shown to play an important role in cytotoxicity of cisplatin, but the frequency of these ternary complexes depends on the cell type and the time of treatment. DPCLs are formed by the transformation of DNA monofunctional and intrastrand cross-links of cisplatin.…”

mentioning

confidence: 97%

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Ahmad

2010

Chemistry & Biodiversity

190

176

View full text Add to dashboard Cite

Platinum-based compounds are widely used as chemotherapeutics for the treatment of a variety of cancers. The anticancer activity of cisplatin and other platinum drugs is believed to arise from their interaction with DNA. Several cellular pathways are activated in response to this interaction, which include recognition by high-mobility group and repair proteins, translesion synthesis by polymerases, and induction of apoptosis. The apoptotic process is regulated by activation of caspases, p53 gene, and several proapoptotic and antiapoptotic proteins. Such cellular processing eventually leads to an inhibition of the replication or transcription machinery of the cell. Deactivation of platinum drugs by thiols, increased nucleotide excision repair of Pt-DNA adducts, decreased mismatch repair, and defective apoptosis result in resistance to platinum therapy. The differences in cytotoxicity of various platinum complexes are attributed to the differential recognition of their adducts by cellular proteins. Cisplatin and oxaliplatin both produce mainly 1,2-GG intrastrand cross-links as major adducts, but oxaliplatin is found to be more active particularly against cisplatin-resistant tumor cells. Mismatch repair and replicative bypass appear to be the processes most likely involved in differentiating the molecular responses to these two agents. This review describes the formation of Pt-DNA adducts, their interaction with cellular components, and biological effects of this interaction.

show abstract

mentioning

confidence: 97%

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Ahmad

2010

Chemistry & Biodiversity

190

176

View full text Add to dashboard Cite

show abstract

“…Cisplatin is one of the most effective chemotherapeutic agents known, displaying clinical activity against a wide range of human tumours, including cancer of the ovary, testis, bladder, lung, head and neck, cervix and endometrium and as a second-line therapy in the treatment of breast cancer (Farrell et al, 2004). The cytotoxic effect of cisplatin is thought to be mediated by its interaction with DNA to form DNA adducts and intrastrand crosslink adducts, which activate several signal transduction pathways that culminate in the induction of apoptotic cell death (Siddik, 2003).…”

mentioning

confidence: 99%

Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo

et al. 2007

View full text Add to dashboard Cite

Titanocene compounds are a novel series of agents that exhibit cytotoxic effects in a variety of human cancer cells in vitro and in vivo. In this study, the antiproliferative activity of two titanocenes (Titanocenes X and Y) was evaluated in human epidermoid cancer cells in vitro. Titanocenes X and Y induce apoptotic cell death in epidermoid cancer cells, with IC50 values that are comparable to cisplatin. Characterisation of the cell death pathway induced by titanocene compounds in A431 cells revealed that apoptosis is preceded by cell cycle arrest and the inhibition of cell proliferation. The induction of apoptosis is dependent on the activation of caspase-3 and -7 but not caspase-8. Furthermore, the antitumour activity of Titanocene Y was tested in an A431 xenograft model of epidermoid cancer. Results indicate that Titanocene Y significantly reduced the growth of A431 xenografts with an antitumour effect similar to cisplatin. These results suggest that titanocenes represent a novel series of promising antitumour agents.

show abstract

“…Consistent with this conclusion is the relatively very low frequency of the DNA-protein ternary CLs produced in Chinese hamster ovary cells treated with cisplatin (Ͻ1%) (Plooy et al, 1984), although other studies revealed somewhat higher amounts of these ternary lesions in other types of tumor cells (Farrell et al, 2004). Adamplatin(II) forms more monofunctional adducts on DNA than cisplatin as a result of retardation of the rearrangement of its monofunctional to bifunctional adducts and favorable competitive reaction with protein.…”

mentioning

confidence: 84%

Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug

Kašpárková¹,

Nováková²,

Vrána³

et al. 2006

Mol Pharmacol

View full text Add to dashboard Cite

The new platinum(IV) complex cis,trans,cis-[PtCl 2 (CH 3 COO) 2 -(NH 3 )(1-adamantylamine)] [adamplatin(IV)] seems promising for the perspective application in therapy of corresponding tumors. It is therefore of great interest to understand details of mechanisms underlying its biological efficacy. Cellular uptake of the drug, alterations in the target DNA induced by platinum drugs along with processing of platinum-induced damage to DNA and drug inactivation by sulfur-containing compounds belong to major pharmacological factors affecting antitumor effects of platinum compounds. We examined in the present work the significance of these factors in the mechanism of antitumor effects of adamplatin(IV) and compared the results with those of the parallel studies performed with "conventional" cisplatin. The results show that deactivation of adamplatin(IV) by sulfurcontaining compounds (such as glutathione or metallothioneins) is likely to play a less significant role in the mechanism of resistance of tumor cells to adamplatin(IV) in contrast to the role of these reactions in the effects of cisplatin. Moreover, the treatment of tumor cells with adamplatin(IV) does not result in DNA modifications that would be markedly different from those produced by cisplatin. In contrast, the effects of other factors, such as enhanced accumulation of the drug in cells, strong inhibition of DNA polymerization by these adducts, lowered DNA repair, and DNA-protein cross-linking are different from the effects of these factors in the mechanism underlying activity of cisplatin. Hence, the differences between effects of adamplatin(IV) and cisplatin observed in the present work on molecular level may help understand the unique activity of adamplatin(IV).Platinum antitumor compounds, such as cisplatin [cis-diamminedichloroplatinum(II)] (Fig. 1A) and its analogs, are widely used in the treatment of testicular and ovarian cancers and a variety of other human solid tumors. Much progress had been made to understand the mechanisms involved in antitumor effects of platinum compounds and drug resistance, which are multifactorial processes (Brabec, 2002;Fuertes et al., 2003). The target for platinum antitumor compounds is DNA, to which they bind efficiently, forming a variety of adducts that block replication and transcription and induce cell death (Johnson et al., 1989). The nature of DNA adducts affects a number of transduction pathways and triggers apoptosis or necrosis in tumor cells (Fuertes et al., 2003). In addition to alterations in the target and processing of platinum-induced damage to DNA, including gene-specific DNA repair pathways, cellular accumulation and inactivation from thiol-containing reductants [e.g., glutathione (GSH) and metallothionein (MT)] belong among further pharmacological factors affecting antitumor effects of platinum compounds that do not operate directly at the level of DNA adducts.Since the introduction of cisplatin, thousands of its bifunctional analogs have been synthesized and evaluated as po- Article, publi...

show abstract

Cytotoxicity, DNA strand breakage and DNA–protein crosslinking by a novel transplatinum compound in human A2780 ovarian and MCF-7 breast carcinoma cells

Cited by 53 publications

References 30 publications

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo

Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug

Contact Info

Product

Resources

About