Cytotoxic Mechanism of XK469: Resistance of Topoisomerase IIβ Knockout Cells and Inhibition of Topoisomerase I

Snapka, Robert M.; Gao, Hanlin; Grabowski, Dale; Brill, David; Chan, Kenneth K.; Li, Ligeng; Li, Gloria C.; Ganapathi, Ram

doi:10.1006/bbrc.2001.4249

Cited by 20 publications

(16 citation statements)

References 14 publications

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“…We also found that the shTII␣ cell line was resistant to mitoxantrone, and to a greater extent compared with ethonafide. Mitoxantrone has been previously shown to inhibit the activity of both topoisomerase II isoforms, with isoform specificity varying between cell culture models (Errington et al, 1999(Errington et al, , 2004Snapka et al, 2001). Overall, our data suggest that topoisomerase II␣ is the primary target for ethonafide in the DU 145 prostate cancer cell line.…”

Section: Mechanism Of Action Of Ethonafide 1115supporting

confidence: 51%

“…This included an evaluation of the cytotoxicity of the topoisomerase II poison XK469, which has been shown to have an increased affinity for topoisomerase II␤ in cell-free assays and in cell culture (Gao et al, 1999;Snapka et al, 2001). due to the low potency of this agent, only a 3-day exposure cytotoxicity curve was established.…”

Section: Methodsmentioning

confidence: 99%

“…at ASPET Journals on May 10, 2018 jpet.aspetjournals.org down-regulation of both isoforms of topoisomerase II has been shown to render cells resistant to topoisomerase II poisons (Errington et al, 1999;Snapka et al, 2001). In addition to topoisomerase II poisons, Emmons et al (2006) also demonstrated that the decreased expression of topoisomerase II␤ sensitizes cells to melphalan and that the enzyme seems to play a role in the repair of melphalan-induced crosslinks.…”

Section: Mechanism Of Action Of Ethonafide 1115mentioning

confidence: 98%

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Ethonafide-Induced Cytotoxicity Is Mediated by Topoisomerase II Inhibition in Prostate Cancer Cells

Pourpak¹,

Landowski²,

Dorr³

2007

J Pharmacol Exp Ther

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Ethonafide is an anthracene-containing derivative of amonafide that belongs to the azonafide series of anticancer agents. The lack of cross-resistance in multidrug-resistant cancer cell lines and the absence of a quinone and hydroquinone moiety make ethonafide a potentially less cardiotoxic replacement for existing anthracene-containing anticancer agents. For this study, we investigated the anticancer activity and mechanism of ethonafide in human prostate cancer cell lines. Ethonafide was cytotoxic against three human prostate cancer cell lines at nanomolar concentrations. Ethonafide was found to be better tolerated and more effective at inhibiting tumor growth compared with mitoxantrone in a human xenograft tumor regression mouse model. Mechanistically, we found that ethonafide inhibited topoisomerase II activity by stabilizing the enzyme-DNA complex, involving both topoisomerase II␣ and -␤. In addition, ethonafide induced a potent G 2 cell cycle arrest in the DU 145 human prostate cancer cell line. By creating stable cell lines with decreased expression of topoisomerase II␣ or -␤, we found that a decrease in topoisomerase II␣ protein expression renders the cell line resistant to ethonafide. The decrease in sensitivity to ethonafide was associated with a decrease in DNA damage and an increase in DNA repair as measured by the neutral comet assay. These data demonstrate that ethonafide is a topoisomerase II poison and that it is topoisomerase II␣-specific in the DU 145 human prostate cancer cell line.

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Section: Mechanism Of Action Of Ethonafide 1115supporting

confidence: 51%

Section: Methodsmentioning

confidence: 99%

Section: Mechanism Of Action Of Ethonafide 1115mentioning

confidence: 98%

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Ethonafide-Induced Cytotoxicity Is Mediated by Topoisomerase II Inhibition in Prostate Cancer Cells

Pourpak¹,

Landowski²,

Dorr³

2007

J Pharmacol Exp Ther

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“…Both of the XK469 enantiomers induce reversible protein-DNA cross-links, thus stabilizing the DNA strand passing intermediates in the topoisomerase reaction. In vitro studies showed that the R(ϩ)-enantiomer was about twice as active as the S-enantiomer (Snapka et al, 2001), with no significant interinversion found for the enantiomers in that system. The R(ϩ)-XK469 has recently been selected for clinical evaluation by the National Cancer Institute.…”

Section: Xk469mentioning

confidence: 97%

“…In a screen for solid tumor-selective agents, it was found that XK469 possesses broad activity against murine solid tumors and human xenografts (Corbett et al, 1998;LoRusso et al, 1999). Its mechanism of antitumor activity has recently been elucidated as a selective topoisomerase II␤ poison (Gao et al, 1999;Snapka et al, 2001). Both of the XK469 enantiomers induce reversible protein-DNA cross-links, thus stabilizing the DNA strand passing intermediates in the topoisomerase reaction.…”

mentioning

confidence: 99%

Chiral Pharmacokinetics and Inversion of Enantiomers of a New Quinoxaline Topoisomerase IIβ Poison in the Rat

Zheng

Jiang²,

Chiu³

et al. 2002

Drug Metab Dispos

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ABSTRACT:XK469 (NSC 697887; (؎)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid), an analog of the herbicide Assure, which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase II␤ poison. Both R(؉) and S(؊) isomers are cytotoxic, although the R-isomer is more potent. Using a chiral highperformance liquid chromatography assay, pharmacokinetics of R(؉)-, S(؊)-, and (؎)-XK469 in Fischer-344 rats were investigated following their separate i.v. administrations. S(؊)-XK469 was found to be predominantly converted to the R-isomer in circulation when the S-isomer was administered either alone or as a racemic mixture. No trace of the S-isomer was found in circulation or in urine or feces, following the R-isomer administration, up to 72 h. In the rat, the plasma concentration-time profiles for both isomers follow a two-compartment pharmacokinetics with the mean t 1/2␤ for the R-isomer of 24.7 h being significantly longer than 4.2 h, the mean t 1/2␤ for the S-isomer. The mean total clearance of the S-isomer was over 200-fold more rapid than that of the R-isomer, and the major clearance route of the S-enantiomer was inversion to its antipode, as estimated by the fractional formation clearance of R(؉)-XK469 of 0.93. Protein binding for both enantiomers was in the range of 95 to 98%. Urinary and fecal elimination in 72 h as the intact drug were 7 to 10% and 8% of the administered dose, respectively, either administered as the individual enantiomers or as a racemate. Cumulative biliary elimination in 7 h was about 3% of the dose. No evidence of enantiomeric interaction at the pharmacokinetic level was detected. XK4691 (NSC 697887; (Ϯ)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid) (Fig. 1), is an analog of the herbicide Assure synthesized by DuPont. In a screen for solid tumor-selective agents, it was found that XK469 possesses broad activity against murine solid tumors and human xenografts (Corbett et al., 1998;LoRusso et al., 1999). Its mechanism of antitumor activity has recently been elucidated as a selective topoisomerase II␤ poison (Gao et al., 1999;Snapka et al., 2001). Both of the XK469 enantiomers induce reversible protein-DNA cross-links, thus stabilizing the DNA strand passing intermediates in the topoisomerase reaction. In vitro studies showed that the R(ϩ)-enantiomer was about twice as active as the S-enantiomer (Snapka et al., 2001), with no significant interinversion found for the enantiomers in that system. The R(ϩ)-XK469 has recently been selected for clinical evaluation by the National Cancer Institute.We recently reported a validated chiral HPLC method to analyze the drug concentrations in rat urine and mouse, rat, and dog plasma samples (Zheng et al., 2002). A substantial inversion of the S(Ϫ)-to R(ϩ)-enantiomer was observed in the plasma samples from all three animal species; however, the reverse inversion was not detected, at least not in the rat. Because XK469 is a new antitumor agent, pharmacokin...

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Topoisomerase II Inhibitors: Chemical Biology

Rogojina

Gajewski

Bahmed

et al. 2011

Cancer Drug Discovery and Development

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Cytotoxic Mechanism of XK469: Resistance of Topoisomerase IIβ Knockout Cells and Inhibition of Topoisomerase I

Cited by 20 publications

References 14 publications

Ethonafide-Induced Cytotoxicity Is Mediated by Topoisomerase II Inhibition in Prostate Cancer Cells

Ethonafide-Induced Cytotoxicity Is Mediated by Topoisomerase II Inhibition in Prostate Cancer Cells

Chiral Pharmacokinetics and Inversion of Enantiomers of a New Quinoxaline Topoisomerase IIβ Poison in the Rat

Topoisomerase II Inhibitors: Chemical Biology

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