The Antitumor Triazoloacridone C-1305 Is a Topoisomerase II Poison with Unusual Properties

Lemke, Krzysztof; Poindessous, Virginie; Składanowski, Andrzej; Larsen, Annette K.

doi:10.1124/mol.104.000703

Cited by 40 publications

(49 citation statements)

References 30 publications

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“…On the other hand, UGT1A10 expression slightly but significantly decreased the cellular response to C-1311, suggesting that the glucuronide metabolite of C-1311 may have lower activity than the parent compound. Thus, despite the subtle differences in structure and chemical properties between imidazoacridinones and triazoloacridinones (Lemke et al, 2004;Fedejko-Kap et al, 2012), the finding that the glucuronide of C-1305 is more toxic than the parent compound may be an important factor to be considered in evaluation of the clinical value and application of C-1305 versus C-1311. The differential cytotoxicities of the respective glucuronides are certainly intriguing given that the 8-OH group is in the structurally conserved portion of the molecules (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Despite their clinical potential, the biologic and biochemical mechanisms of C-1305 and C-1311 action are still under extensive study (Mazerska et al, 2001(Mazerska et al, , 2003Augustin et al, 2006;Skwarska et al, 2007). Both compounds intercalate to DNA and inhibit topoisomerase II activity (Skladanowski et al, 1996;Dziegielewski et al, 2002;Lemke et al, 2004;Koba and Konopa, 2007). Furthermore, the lethal actions of these drugs appear to be due to covalent DNA cross-linking occurring only after metabolic activation (Dziegielewski and Konopa, 1996;Koba and Konopa, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Transformation of Antitumor Acridinone C-1305 but Not C-1311 via Selective Cellular Expression of UGT1A10 Increases Cytotoxic Response: Implications for Clinical Use

et al. 2012

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The acridinone derivates 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) and 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) are promising antitumor agents with high activity against several experimental cellular and tumor models and are under evaluation in preclinical and early phase clinical trials. Recent evidence from our laboratories has indicated that both compounds were conjugated by several uridine diphosphate-glucuronyltransferase (UGT) isoforms, the most active being extrahepatic UGT1A10. The present studies were designed to test the ability and selectivity of UGT1A10 in the glucuronidation of acridinone antitumor agents in a cellular context. We show that in KB-3 cells, a HeLa subline lacking expression of any UGT isoforms, both C-1305 and C-1311 undergo metabolic transformation to the glucuronidated forms on overexpression of UGT1A10. Furthermore, UGT1A10 overexpression significantly increased the cytotoxicity of C-1305, but not C-1311, suggesting that the glucuronide was more potent than the C-1305 parent compound. These responses were selective for UGT1A10 because documented overexpression of UGT2B4 failed to produce glucuronide products and failed to alter the cytotoxicity for both compounds. These findings contribute to our understanding of the mechanisms of action of these agents and are of particular significance because data for C-1305 contradict the dogma that glucuronidation typically plays a role in detoxification or deactivation. In summary, these studies suggest that extrahepatic UGT1A10 plays an important role in the metabolism and the bioactivation of C-1305 and constitutes the basis for further mechanistic studies on the mode of action of this drug, as well as translational studies on the role of this enzyme in regulation of C-1305 toxicity in cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolic Transformation of Antitumor Acridinone C-1305 but Not C-1311 via Selective Cellular Expression of UGT1A10 Increases Cytotoxic Response: Implications for Clinical Use

et al. 2012

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“…Analysis of variance (two-way analysis of variance with Bonferroni post hoc analysis) was performed using GraphPad Prism (GraphPad Software Inc.). has been shown to influence specific interactions of C-1305 with DNA (Lemke et al, 2004). Therefore, one can suspect that changes in the electron density of the heterocyclic ring supported by the longer distance between the amino groups in the side chain as well as by the presence of more easily dealkylated methyl group are responsible for C-1305 being a better substrate for UGTs.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that both compounds intercalate to DNA; however, physicochemical DNA binding is not crucial for the observed antitumor activity of these compounds (Dziegielewski et al, 2002;Koba and Konopa, 2007). It is postulated that the anticancer properties of these compounds are related to their inhibition of topoisomerase II activity (Skladanowski et al, 1996;Lemke et al, 2004) and interstrand covalent DNA cross-linking in tumor cells by metabolically activated compounds (Dziegielewski and Konopa, 1996;Koba and Konopa, 2007).…”

Section: Introductionmentioning

confidence: 99%

Role of Human UDP-Glucuronosyltransferases in the Biotransformation of the Triazoloacridinone and Imidazoacridinone Antitumor Agents C-1305 and C-1311: Highly Selective Substrates for UGT1A10

Fedejko-Kap

Bratton²,

Finel³

et al. 2012

Drug Metab Dispos

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ABSTRACT:5-Diethylaminoethylamino-8-hydroxyimidazoacridinone, C-1311 (NSC-645809), is an antitumor agent shown to be effective against breast cancer in phase II clinical trials. A similar compound, 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, shows high activity against experimental tumors and is expected to have even more beneficial pharmacological properties than C-1311. Previously published studies showed that these compounds are not substrates for cytochrome P450s; however, they do contain functional groups that are common targets for glucuronidation. Therefore, the aim of this work was to identify the human UDP-glucuronosyltransferases (UGTs) able to glucuronidate these two compounds. High-performance liquid chromatography analysis was used to examine the activities of human recombinant UGT1A and UGT2B isoforms and microsomes from human liver [human liver microsomes ( . In summary, these studies suggest that imid azoacridinone and triazoloacridinone drugs are glucuronidated in human liver and intestine in vivo and may form the basis for future translational studies of the potential role of UGTs in resistance to these drugs.

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“…C-1305 exhibits significant cytotoxic activity in vitro and potent antitumor activity towards a wide range of experimental tumors in mice (particularly leukemias, colon cancers and melanomas) [7] . This drug is a DNA topoisomerase II inhibitor that stabilizes covalent complexes between DNA and the topoisomerase enzyme [8] . Compared to classic topoisomerase II inhibitors, such as amsacrine, C-1305 produces only low levels of cleavable complexes.…”

Section: Introductionmentioning

confidence: 99%

CYP3A4 overexpression enhances the cytotoxicity of the antitumor triazoloacridinone derivative C-1305 in CHO cells

et al. 2012

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Aim: To examine how the higher expression level of CYP3A4 isoenzyme influenced the cytotoxicity of the antitumor triazoloacridinone derivative C-1305 in Chinese hamster ovary (CHO) cells. Methods: Three CHO cell lines were examined: wild-type CHO cells; CHO-HR cells with overexpression of human cytochrome P450 reductase (CPR); and CHO-HR-3A4 cells with coexpression of human CYP3A4 and CPR. Cellular responses caused by C-1305 were monitored using DAPI staining, cell cycle analysis, phosphatydilserine externalization analysis and SA-β-galactosidase expression analysis. Cell viability was assessed with simultaneous FDA and PI staining.

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The Antitumor Triazoloacridone C-1305 Is a Topoisomerase II Poison with Unusual Properties

Cited by 40 publications

References 30 publications

Metabolic Transformation of Antitumor Acridinone C-1305 but Not C-1311 via Selective Cellular Expression of UGT1A10 Increases Cytotoxic Response: Implications for Clinical Use

Metabolic Transformation of Antitumor Acridinone C-1305 but Not C-1311 via Selective Cellular Expression of UGT1A10 Increases Cytotoxic Response: Implications for Clinical Use

Role of Human UDP-Glucuronosyltransferases in the Biotransformation of the Triazoloacridinone and Imidazoacridinone Antitumor Agents C-1305 and C-1311: Highly Selective Substrates for UGT1A10

CYP3A4 overexpression enhances the cytotoxicity of the antitumor triazoloacridinone derivative C-1305 in CHO cells

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