Altered stability of etoposide-induced topoisomerase II-DNA complexes in resistant human leukaemia K562 cells

Ritke, Mary K.; Roberts, DeWayne; Allan, William P.; Raymond, Jacques; Bergoltz, Vladimir V.; Yalowich, Jack C.

doi:10.1038/bjc.1994.131

Cited by 63 publications

(82 citation statements)

References 55 publications

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“…However, like kinamycin A and kinamycin C, the lack of kinamycin F cross resistance towards the K/VP.5 cell line (Fig. 7B), which contains one-fifth the amount of topoisomerase IIα compared to the parent K562 cell line [15,16], suggested that kinamycin F, like kinamycin A and kinamycin C [13], did not function as a topoisomerase II poison in cells. We and others have shown that topoisomerase IIα is highly sensitive to sulfhydryl-reactive drugs such as quinones [35,36] and cisplatin [21].…”

Section: Discussionmentioning

confidence: 99%

“…To determine whether kinamycin F acts as a topoisomerase II poison, a comparison of the growth inhibitory effects of kinamycin F on K562 and the K/VP.5 cell lines was used. The K/VP.5 cell line contains one-fifth the amount of topoisomerase IIα compared to the parent K562 cell line [15,16], and can be a convenient test of whether a compound is a topoisomerase II poison [21]. Fewer DNA strand breaks will be produced in cells containing less topoisomerase II and thus, topoisomerase II poisons will be less potent towards the K/VP.5 cell line.…”

Section: Kinamycin F Inhibits Topoisomerase II Catalytic Activity Butmentioning

confidence: 99%

“…5 cells (a 26-fold etoposide-resistant K562-derived cell line with decreased levels of topoisomerase IIα protein and mRNA) [15,16] were maintained as suspension cultures in Dulbecco's modified Eagle's medium (Invitrogen, Burlington, Canada) containing 4 mM Lglutamine and supplemented with 20 mM HEPES, 10% fetal calf serum (Invitrogen), 100 units/ ml penicillin G, and 100 μg/ml streptomycin in an atmosphere of 5% CO 2 and 95% air at 37°C (pH 7.4).…”

Section: Cell Culture and Growth Inhibition Assaysmentioning

confidence: 99%

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Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

O’Hara

Patel

et al. 2007

Free Radical Biology and Medicine

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The bacterial metabolite kinamycin F, which is being investigated as a potent antitumor agent, contains an unusual and potentially reactive diazo group as well as a paraquinone and a phenol functional group. Kinamycin F reacted with glutathione (GSH) in a complex series of reactions which suggested that kinamycin F may have its cytotoxicity modulated by GSH. Consistent with this idea 2-oxo-4-thiazolidinecarboxylic acid treatment to increase cellular GSH levels and buthionine sulfoximine treatment to decrease GSH levels resulted in decreased and increased kinamycin F cytotoxicity, respectively, in K562 leukemia cells. Kinamycin F weakly bound to DNA and induced DNA damage in K562 cells that was independent of GSH levels. The GSH-promoted DNA nicking induced by kinamycin F in vitro was attenuated by deferoxamine, dimethyl sulfoxide, and by catalase, which indicated that DNA damage initiated by this agent occurred in an iron-, hydrogen peroxideand hydroxyl radical-dependent manner. Electron paramagnetic resonance spectroscopy experiments showed that the GSH/kinamycin F system produced a semiquinone free radical and that the hydrogen peroxide/peroxidase/kinamycin F system generated a phenoxyl free radical. In conclusion, the results indicated that kinamycin F cytotoxicity may be due to reductive and/or peroxidative activation to produce DNA-and protein-damaging species.

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Section: Discussionmentioning

confidence: 99%

Section: Kinamycin F Inhibits Topoisomerase II Catalytic Activity Butmentioning

confidence: 99%

Section: Cell Culture and Growth Inhibition Assaysmentioning

confidence: 99%

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Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

O’Hara

Patel

et al. 2007

Free Radical Biology and Medicine

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“…6 in which it was shown that the K/VP.5 cell line that has a 5-fold lower level of topoisomerase II␣ (Ritke and Yalowich, 1993;Ritke et al, 1994a) displayed minimal decreased sensitivity to cisplatin. It should be noted that because K/VP.5 cells were selected for resistance to etoposide (Ritke et al, 1994b), the adaptation of these cells may include events other than reduction of topoisomerase II␣ levels, such as reduced topoisomerase II␣ phosphorylation (Ritke et al, 1994a), altered stability of drug-induced topoisomerase II␣-DNA covalent complexes (Ritke et al, 1994b), and other undocumented genetic changes that may influence the resistance patterns to cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and Proteomics Approaches to Characterize Topoisomerase IIα Cysteines and DNA as Targets Responsible for Cisplatin-Induced Inhibition of Topoisomerase IIα

Hasinoff¹,

Wu²,

Krokhin³

et al. 2004

Mol Pharmacol

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Cisplatin was shown to strongly inhibit the decatenation and relaxation activity of isolated human DNA topoisomerase II␣. This inhibition was not accompanied by stabilization of a covalent topoisomerase II␣-DNA intermediate. Pretreatment of kinetoplast plasmid DNA (kDNA) or pBR322 DNA with submicromolar concentrations of cisplatin quickly rendered these substrates incompetent in the topoisomerase II␣ catalytic assay. Cisplatin nearly equally inhibited growth of a parental K562 and an etoposide-resistant K/VP.5 cell line that contained decreased topoisomerase II␣ levels, a result consistent with isolated enzyme experiments demonstrating that cisplatin was not a topoisomerase II␣ poison. Because cisplatin is known to react with protein sulfhydryl groups, the 13 cysteine groups in the topoisomerase II␣ monomer were evaluated by mass spectrometry to determine which cysteines were free and disulfide-bonded to identify possible sites of cisplatin adduction. High-pressure liquid chromatographymatrix-assisted laser desorption ionization mass spectrometry showed that topoisomerase II␣ contained at least five free cysteines (170, 216, 300, 392, and 405) and two disulfide-bonded cysteine pairs (427-455 and 997-1008). Cysteine 733 was also disulfide-bonded, but its partner cysteine could not be identified. Cisplatin antagonized the formation of a fluorescence adduct between topoisomerase II␣ and the sulfhydryl-reactive maleimide reagent 10-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-9-methoxy-3-oxo-3H-naphtho[2,1-b]pyran-2-carboxylic acid methyl ester (ThioGlo-1). Dithiothreitol, which was shown by spectrophotometry to react rapidly with cisplatin (6-min half-time), diminished the capacity of cisplatin to interfere with ThioGlo-1 binding to topoisomerase II␣. The results of this study suggest that cisplatin may exert some of its cell growth inhibitory and antitumor activity by inhibition of topoisomerase II␣ through reaction with critical enzyme sulfhydryl groups and/or by forming DNA adducts that render the DNA substrate refractory to topoisomerase II␣.Cisplatin is widely used for the treatment of cancer and is thought to act by forming intrastrand and interstrand crosslinks with DNA (Waud, 1995;Reedijk, 1996). A variety of other biomolecules have also been shown to react with cisplatin because of its electrophilicity toward sulfhydryl, methionine, histidine, and other amino acids with nitrogencontaining side chains (Waud, 1995;Reedijk, 1996;Ivanov et al., 1998;Hagrman et al., 2003). In a study of the topoisomerase II inhibitory effects of a platinum(II) complex of the catalytic topoisomerase II inhibitor dexrazoxane, we showed that cisplatin strongly inhibited the decatenation activity of topoisomerase II (Hasinoff et al., 2004). Topoisomerase II alters DNA topology by catalyzing the passing of an intact DNA double helix through a transient double-stranded break made in a second helix and is critical for relieving torsional Article, publication date, and citation information can be found at http://molpharm.aspetjournal...

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“…Topoisomerase II-DNA covalent complex formation in intact cells was measured as described previously (28). Mid-log growth CHO and DZR cells were labeled for 24 hr with 0.5 Ci/ml [methyl-…”

Section: Methodsmentioning

confidence: 99%

Mitindomide Is a Catalytic Inhibitor of DNA Topoisomerase II That Acts at the Bisdioxopiperazine Binding Site

et al. 1997

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SUMMARYThe antitumor drug mitindomide (NSC 284356) was shown to inhibit the decatenation activity of human and Chinese hamster ovary (CHO) topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.1]. Mitindomide did not induce the formation of topoisomerase II-DNA covalent cleavable complexes in CHO cells. These results taken together indicate that mitindomide is a catalytic/noncleavable complex-forming-type inhibitor of topoisomerase II. The growth inhibitory effects of mitindomide and dexrazoxane toward a sensitive parent CHO cell line and the dexrazoxane-resistant DZR cell line, which is highly (500-fold) resistant to the bisdioxopiperazine dexrazoxane, were measured. The DZR cell line was shown to be 30-fold cross-resistant to mitindomide. Mitindomide, like dexrazoxane, was shown to inhibit cleavable complex formation by the topoisomerase II poison etoposide. The attenuated inhibition of etoposide-induced cleavable complexes in DZR compared with CHO cells was, likewise, very similar for dexrazoxane and mitindomide. Together these results suggest that mitindomide acts at the same site on topoisomerase II as does dexrazoxane and other bisdioxopiperazines. Various molecular parameters obtained by molecular modeling were compared for mitindomide and dexrazoxane. Mitindomide, which is conformationally very rigid, has highly coplanar imide rings, as does dexrazoxane in the solid state. Other molecular parameters, such as the imide nitrogen-to-imide nitrogen bond distances, and polar and nonpolar surface areas were also very similar. Thus, it is concluded that mitindomide exerts its antitumor effects through its inhibition of topoisomerase II by binding to the bisdioxopiperazine binding site.Mitindomide (NSC 284356) (Fig. 1) and a number of its analogs have been shown to have good antitumor activity (1-3). Even though mitindomide has been shown to slowly (over 12 hr) promote DNA-interstrand cross-linking (4), the mechanism by which mitindomide or its analogs exert their antitumor effects has never been identified. Problems with low aqueous solubility of mitindomide (3, 5, 6) led to the development of a number of more soluble N-substituted analogs (3, 4, 7-9), some of which also displayed good antitumor activity. The N-substituted mitindomide analog fetindomide (NSC 373965) has been shown (10) to hydrolyze to mitindomide, suggesting that mitindomide is the active form of fetindomide.The bisdioxopiperazine dexrazoxane (Fig. 1), like mitindomide, is also a bis imide. We and others have shown that the bisdioxopiperazines dexrazoxane (ICRF-187; Zinecard, ADR-529) (Fig. 1), ICRF-159 (razoxane, the racemic form of dexrazoxane), and ICRF-193 (Fig. 1) are strong inhibitors of mammalian topoisomerase II (11,12). Razoxane was developed originally as an antitumor agent (13). Dexrazoxane is, however, now clinically used for the prevention of doxorubicininduced cardiotoxicity (14), and presumably acts through its EDTA-like hydrolysis product (15) by inhibiting iron-dependent oxygen free radical formation.Topoisomerase II...

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Altered stability of etoposide-induced topoisomerase II-DNA complexes in resistant human leukaemia K562 cells

Cited by 63 publications

References 55 publications

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

Biochemical and Proteomics Approaches to Characterize Topoisomerase IIα Cysteines and DNA as Targets Responsible for Cisplatin-Induced Inhibition of Topoisomerase IIα

Mitindomide Is a Catalytic Inhibitor of DNA Topoisomerase II That Acts at the Bisdioxopiperazine Binding Site

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