Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A

Sava, Gianni; Bergamo, Alberta; Zorzet, Sonia; Gava, Barbara; Casarsa, Claudia; Cocchietto, Moreno; Furlani, A.; Scarcia, V.; Serli, Barbara; Iengo, Elisabetta; Alessio, Enzo; Mestroni, G.

doi:10.1016/s0959-8049(01)00389-6

Cited by 212 publications

(186 citation statements)

References 7 publications

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“…31,32,33 Also, complete reduction of NAMI-A with equivalent amounts of ascorbic acid, glutathione or cysteine resulted in a more active Ru(II) species than NAMI-A against mice bearing advanced MCa mammary carcinoma. 34 Growth inhibition of the human ovarian cancer cell line A2780 by Ru(II)-arene complexes of the type [X( 6 -arene)(en)Ru(II)] was reported, apparently by a mechanism different from that of Ru(III) complexes. 33 Thus, we investigated the potential antitumor activity of stable Ru(II) complexes that do not need to be reduced but are related to NAMI in that they contain imidazole-type ligands such as KTZ and CTZ, which have themselves displayed some activity in their uncomplexed form.…”

Section: Discussionmentioning

confidence: 99%

“…Cytochrome P-450 isoforms CYP1A2, 2B1, 2C11 and 3A2 produced hydroxyl radicals, an effect counteracted by free KTZ in vivo. 38 We postulate that redox imbalance, including that induced by Ru(II), 26,[31][32][33][34] may produce free radicals in which complexed RuCl 2 (KTZ) 2 is less effective than free KTZ as a cytochrome P-450 inhibitor 2 and as a scavenger to protect from oxidative stress and death. 38 In summary, the concept behind cancer treatment has evolved over the past decade from systemic, nonspecific, high-dose chemotherapy to targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

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Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

Anzellotti

Sánchez‐Delgado

Rieber

2004

Intl Journal of Cancer

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KTZ, originally developed as an antifungal agent, exhibits concentration-dependent inhibitory and potentiating effects on microtubule drugs like vinblastine at concentration ranges near plasma levels of KTZ attained in human subjects. 1 KTZ is a cytochrome P-450 inhibitor that inhibits adrenal steroidogenesis 2 and shows antiglucocorticoid activity. 3 KTZ synergizes with docetaxel in the treatment of hormone-dependent cancer. 4 This finding was preceded by a report that KTZ exerts a cytostatic effect on human prostate cancer cell lines resistant to microtubule-active drugs, like vinblastine and paclitaxel, and enhances the response to these drugs. 5 Among the mechanisms involved in its anticarcinoma action, it has been reported that KTZ induces apoptosis through a p53-dependent pathway 6 and induces G 0 /G 1 arrest 7 in colorectal and hepatocellular carcinoma lines. Another azole derivative which shows potentially useful antitumor activity is CTZ, recognized as a calmodulin antagonist and inhibitor of glycolysis and known to be the primary energy source in most cancer cells. 8 CTZ induced significant reduction in glycolysis and ATP levels, which led to tumor cell destruction after 3 hr. 8 There is a need to enhance the efficacy of potentially useful anticancer agents like KTZ and CTZ and to develop new compounds capable of activity against tumor cells refractory to apoptosis since the latter property usually correlates with drug resistance.Since genetic alterations involving p53 mutation frequently correlate with decreased response to cancer chemotherapy, 9,10 we investigated whether Ru(II) complexes with CTZ or KTZ 11-13 are more effective than the parent compounds at promoting cell death in tumors with such genetic changes. The reason for this study with Ru(II)-azole complexes is to expand the range of potentially useful antitumor Ru agents since an Ru(III) complex like NAMI-A, 14 -16 which may require reduction of its Ru(III) moiety to act, has shown promising anticancer activity in initial clinical trials. 15 The effects of NAMI-A are often compared to the widely known anticancer drug cisplatin, similarly based on another transition metal. 17 Interestingly, most of the Ru complexes tested to date, including NAMI-A, have not been strikingly more cytotoxic than cisplatin, the most appropriate reference control. 17 While the effect of NAMI-A on metastasis inhibition was previously described in several models, 14,15 its mechanism of action was demonstrated only recently. In vitro studies showed that 100 M NAMI-A, active on lung tumor metastases, 14 induced apoptosis of a transformed ECV304 human endothelial cell line by promoting caspase-3 activation 16 and release of mitochondrial cytochrome c, 16,18 hallmarks of cellular suicide. The mitochondrial damage induced by NAMI-A 16 is compatible with the effect of 20 -50 M CTZ, which induces glycolysis-related hexokinase detachment from mitochondria and loss of viability in B16 melanoma. 8 Since apoptosis induced by 50 M KTZ is decreased in colorectal and hepatocellu...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

Anzellotti

Sánchez‐Delgado

Rieber

2004

Intl Journal of Cancer

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“…The evidence that both these compounds readily interact with biological reductants [9,10,11] has suggested that the reduction of the Ru(III) pro-drug to Ru(II) is a required step to accomplish their biological activity (the so-called activation-by-reduction hypothesis) [12,13]. According to this suggestion, the anticancer potential of Ru(II) compounds has been explored.…”

Section: Introductionmentioning

confidence: 99%

A QM/MM study of the binding of RAPTA ligands to cathepsin B

Ciancetta

Genheden

Ryde

2011

J Comput Aided Mol Des

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“…The same holds true for ruthenium coordination compounds, and this kinetic behavior makes such compounds very useful. Although several ruthenium compounds have been reported to show antitumor behavior in cell-line studies (22)(23)(24)(25), only one of them has entered clinical trials so far (26). It should be noted that Ru compounds are intrinsically octahedrally coordinated, and even though a cis chelate is possible, the space that axial ligands require prevent it from forming similar structures with DNA as Pt(II) compounds can (Fig.…”

mentioning

confidence: 99%

New clues for platinum antitumor chemistry: Kinetically controlled metal binding to DNA

Reedijk

2003

Proc. Natl. Acad. Sci. U.S.A.

579

349

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Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A

Cited by 212 publications

References 7 publications

Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

A QM/MM study of the binding of RAPTA ligands to cathepsin B

New clues for platinum antitumor chemistry: Kinetically controlled metal binding to DNA

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