New platinum(IV) complex with adamantylamine ligand as a promising anti-cancer drug: comparison of in vitro cytotoxic potential towards A2780/cisR cisplatin-resistant cell line within homologous series of platinum(IV) complexes

Tuřánek, Jaroslav; Kašná, Andrea; Záluská, Dana; Neča, Jiřı́; Kvardová, Veronika; Knotigová, Pavlína Turánek; Horváth, Viktor; Šindlerová, Lenka; Kozubı́k, Alois; Sova, Petr; Kroutil, Aleš; F, Zak; Mistr, A.

doi:10.1097/01.cad.0000127147.57796.e5

Cited by 37 publications

(35 citation statements)

References 7 publications

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“…Adamplatin(IV) proved to be quite toxic to the tumor cells, with IC 50 values that were markedly lower than those observed for cisplatin and JM216 (Turanek et al, 2004;Kozubík et al, 2005). The origin of this effect may be multifactorial.…”

Section: Discussionmentioning

confidence: 95%

“…A possible explanation for the difference in cytotoxicity between cisplatin and the complexes containing alkylamine ligands with increased hydrophobicity, such as JM216 or adamplatin(IV) may be associated with differential cellular uptake of the compounds (Turanek et al, 2004). Cellular uptake of cisplatin and adamplatin(IV) was measured in A2780 and A2780cisR cells (sensitive and resistant to cisplatin, respectively) treated with the platinum compound for 72 h at the concentrations corresponding to the IC 50 values in the cells tested.…”

Section: Resultsmentioning

confidence: 99%

“…1A) exhibited a high cytotoxic effect without cross-resistance to cisplatin in in vitro assays, and the mode of synthesis was acceptable with respect to industrial manufacturing. The evaluation of cytotoxicity of adamplatin(IV) on a panel of cisplatin resistant cancer cell lines revealed a high cytotoxic effect of this drug against leukemic, melanoma, and colorectal cancer cell lines and its high efficiency to trigger apoptosis (Turanek et al, 2004;Kozubík et al, 2005). The cytotoxic effect of adamplatin(IV) on cisplatin-resistant cell lines is rapid and stronger in comparison with cisplatin and JM216 (Turanek et al, 2004).…”

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confidence: 99%

“…The evaluation of cytotoxicity of adamplatin(IV) on a panel of cisplatin resistant cancer cell lines revealed a high cytotoxic effect of this drug against leukemic, melanoma, and colorectal cancer cell lines and its high efficiency to trigger apoptosis (Turanek et al, 2004;Kozubík et al, 2005). The cytotoxic effect of adamplatin(IV) on cisplatin-resistant cell lines is rapid and stronger in comparison with cisplatin and JM216 (Turanek et al, 2004). Thus, adamplatin(IV) seems promising for the perspective application in therapy of corresponding tumors, so it is of great interest to understand details of molecular and biochemical mechanisms underlying the biological efficacy of adamplatin(IV).…”

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confidence: 99%

“…Two years ago, synthesis and cytotoxicity of a series of other platinum(IV) complexes with bulky hydrophobic ligands were reported (Turanek et al, 2004;Kozubík et al, 2005). The complex cis,trans,cis-[PtCl 2 (CH 3 COO) 2 (NH 3 )(1-adamantylamine)] [adamplatin(IV)] (Fig.…”

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

Kašpárková¹,

Nováková²,

Vrána³

et al. 2006

Mol Pharmacol

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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...

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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Kašpárková¹,

Nováková²,

Vrána³

et al. 2006

Mol Pharmacol

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New Trends and Future Developments of Platinum‐Based Antitumor Drugs

Wang

Guo

2011

Bioinorganic Medicinal Chemistry

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Folate–Cyclodextrin Conjugates as Carriers of the Platinum(IV) Complex LA‐12

et al. 2014

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Folic acid has emerged as an interesting cell‐targeting moiety and a number of drugs have been conjugated to folate. In this context, new conjugates of β‐cyclodextrins with folate have been synthesised as drug carriers to improve their selectivity for cells overexpressing the folic acid receptor. In particular, both 3‐ and 6‐functionalised β‐cyclodextrins, linked to the α‐ or γ‐carboxylic group of folic acid, have been synthesised and fully characterised. As a proof of concept, the antitumour platinum(IV) complex cis–trans–cis‐[PtCl2(CH3CO2)2(adamantylamine)(NH3)] (LA‐12) has been used as a guest drug. The LA‐12–cyclodextrin inclusion complexes have been tested on tumour cells. In the presence of cyclodextrin–folate conjugates, LA‐12 exhibited IC50 values four times smaller than those of LA‐12 alone in MDA‐MB‐231 cells, which overexpress folic acid receptors on their membrane. No improvement of LA‐12 cytotoxicity was found in control tumour cells that do not overexpress the folate receptor. Thus, the non‐covalent approach, based on inclusion complexes with functionalised cyclodextrins, looks very promising for drug targeting.

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New platinum(IV) complex with adamantylamine ligand as a promising anti-cancer drug: comparison of in vitro cytotoxic potential towards A2780/cisR cisplatin-resistant cell line within homologous series of platinum(IV) complexes

Cited by 37 publications

References 7 publications

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

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

New Trends and Future Developments of Platinum‐Based Antitumor Drugs

Folate–Cyclodextrin Conjugates as Carriers of the Platinum(IV) Complex LA‐12

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