Metal Antitumor Compounds: The Mechanism of Action of Platinum Complexes

Johnson, Neil P.; Butour, Jean‐Luc; Villani, Giuseppe; Wimmer, Franz Martin; Defais, Martine; Pierson, V.; Brabec, Viktor

doi:10.1007/978-3-642-74760-1_1

Cited by 163 publications

(126 citation statements)

References 140 publications

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“…The cytotoxic effects of antitumor platinum drugs might arise from a number of mechanisms, including tumor cell accumulation, protein interacions, DNA modifications and their cellular processing (34,43,44). To support the view that DNA is a potential target for photoactivated 1, platinum levels on nuclear DNA were determined after exposure of A2780 tumor cells to 1 photoactivated by UVA.…”

Section: Discussionmentioning

confidence: 99%

Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells

Prachařová

Zerzánková

Štěpánková

et al. 2012

Chem. Res. Toxicol.

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The Pt IV diazido complex trans,trans,trans-[Pt-(N 3 ) 2 (OH) 2 (pyridine) 2 ] (1) is unreactive in the dark but is cytotoxic when photoactivated by UVA and visible light. We have shown that 1 when photoactivated accumulates in tumor cells and binds strongly to nuclear DNA under conditions in which it is toxic to tumor cells. The nature of the DNA adducts, including conformational alterations, induced by photoactivated 1 are distinctly different from those produced in DNA by conventional cisplatin or transplatin. In addition, the observation that major DNA adducts of photoactivated 1 are able to efficiently stall RNA polymerase II more efficiently than cisplatin suggests that transcription inhibition may contribute to the cytotoxicity levels observed for photoactivated 1. Hence, DNA adducts of 1 could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. The findings of the present work help to explain the different cytotoxic effects of photoactivated 1 and conventional cisplatin and thereby provide new insights into mechanisms associated with the antitumor effects of platinum complexes photoactivated by UVA and visible light.

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Section: Discussionmentioning

confidence: 99%

Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells

Prachařová

Zerzánková

Štěpánková

et al. 2012

Chem. Res. Toxicol.

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“…The mechanism of anticancer activity involves formation of platinum-DNA adducts that are capable of inhibiting DNA and RNA synthesis (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) and inducing programmed cell death (17,18). Cisplatin binds preferentially to the N7 position of purine residues.…”

mentioning

confidence: 99%

“…The monofunctional adduct subsequently closes to a bifunctional adduct by linking a second purine that can be either of the same strand or of the opposite strand (19). There is general consensus that the antitumor efficacy of cisplatin is associated with the formation of DNA 1,2-intrastrand d(GpG) or d(ApG) cross-links (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The 1,2-intrastrand crosslinks locally unwind and bend doublestranded DNA toward the major groove (14,20,21), and the disturbance of DNA secondary structure seems to be the ultimate reason for inhibition of DNA replication and/or transcription and for triggering apoptotic cell death (22,23).…”

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confidence: 99%

Chiral discrimination in platinum anticancer drugs.

Benedetti

Malina

Kašpárková

et al. 2002

Environ Health Perspect

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In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

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“…It should be noted that besides the common use of cisplatin many patients develop resistance to this drug and numerous side effects occur, such as organ toxicity e.g. nephrotoxicity, reduction in the number of bone marrow cells and increased risk of deep vein thrombosis [6,7]. Therefore, new platinum derivatives and complexes are being searched for.…”

Section: Introductionmentioning

confidence: 99%

Anticancer activity of a trans-platinum(II) complex of 3-aminoflavone to ovarian cancer cells

Orzechowska

Fabijańska²,

Ochocki³

et al. 2017

Ginekol Pol

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Objectives: Cisplatin is a classical anticancer drug used in the treatment of ovarian cancer. Unfortunately, the treatment is associated with numerous adverse effects. Studies concerning new platinum derivatives with less organ toxicity are conducted. The aim of this study was to analyse the effect of a new trans-platinum(II) complex of 3-aminoflavone on the viability and mortality of the cells from OVCAR 3 and CAOV 3 ovarian cancer cell lines and on the expression of the selected genes involved in the process of apoptosis. Material and methods:The viability of ovarian cancer cells and the cytotoxicity of a trans-platinum(II) complex of 3-aminoflavone: [trans-Pt(3-af ) 2 Cl 2 ), trans-bis-(3-aminoflavone) dichloridoplatinum(II)] and cisplatin were analysed using a spectrophotometric method with the use of MTT assay and LDH assay. BAX, BCL2, BIRC5 gene expression analysis on mRNA level was conducted with the use of Real-Time PCR method.Results: It was observed that parallel to an increase in the concentration of the new complex compound and cisplatin there is a decrease in viability and an increase in mortality of ovarian cancer cells. As a result of exposure to the studied compound and cisplatin, an increased BAX gene expression and decreased BCL2 and BIRC5 gene expression were observed in the studied ovarian cancer cell lines. Conclusion:Trans-Pt(3-af ) 2 Cl 2 exhibits anticancer activity towards OVCAR 3 and CAOV 3 ovarian cancer cell lines. The studied complex compound can be considered as a potential anticancer drug.

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Metal Antitumor Compounds: The Mechanism of Action of Platinum Complexes

Cited by 163 publications

References 140 publications

Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells

Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells

Chiral discrimination in platinum anticancer drugs.

Anticancer activity of a trans-platinum(II) complex of 3-aminoflavone to ovarian cancer cells

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