Possible role of DT-diaphorase in the bioactivation of antitumor quinones

Talcott, Ronald E.; Rosenblum, Michael D.; Levin, V. A.

doi:10.1016/s0006-291x(83)80158-2

Cited by 37 publications

(10 citation statements)

References 4 publications

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“…This enzyme-mediated quinone reduction process has been reported for other quinone-containing molecules, including a number of quinone-based anti-cancer agents (22)(23)(24). In addition, it has also been proposed that 17-AAG is a substrate for NADPH-quinone oxidoreductase 1 (NQO1) (25,26).…”

Section: Ipi-504 and 17-aag Interconvert In Vitro And In Vivomentioning

confidence: 74%

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Sydor

Normant

Pien

et al. 2006

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

220

160

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Heat shock protein 90 (Hsp90) is an emerging therapeutic target of interest for the treatment of cancer. Its role in protein homeostasis and the selective chaperoning of key signaling proteins in cancer survival and proliferation pathways has made it an attractive target of small molecule therapeutic intervention. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), the most studied agent directed against Hsp90, suffers from poor physical-chemical properties that limit its clinical potential. Therefore, there exists a need for novel, patient-friendly Hsp90-directed agents for clinical investigation. IPI-504, the highly soluble hydroquinone hydrochloride derivative of 17-AAG, was synthesized as an Hsp90 inhibitor with favorable pharmaceutical properties. Its biochemical and biological activity was profiled in an Hsp90-binding assay, as well as in cancer-cell assays. Furthermore, the metabolic profile of IPI-504 was compared with that of 17-AAG, a geldanamycin analog currently in clinical trials. The anti-tumor activity of IPI-504 was tested as both a single agent as well as in combination with bortezomib in myeloma cell lines and in vivo xenograft models, and the retention of IPI-504 in tumor tissue was determined. In conclusion, IPI-504, a potent inhibitor of Hsp90, is efficacious in cellular and animal models of myeloma. It is synergistically efficacious with the proteasome inhibitor bortezomib and is preferentially retained in tumor tissues relative to plasma. Importantly, it was observed that IPI-504 interconverts with the known agent 17-AAG in vitro and in vivo via an oxidation-reduction equilibrium, and we demonstrate that IPI-504 is the slightly more potent inhibitor of Hsp90.T he heat shock response, first identified in 1962 by Ritossa (1), was initially characterized as the induction of select polypeptides in response to an acute cellular heat shock. These polypeptides were proteins that bound to partially unfolded proteins to prevent their aggregation and assist in their refolding (2, 3), and were termed chaperones. Of the heat shock proteins, heat shock protein 90 (Hsp90) in particular has been the subject of intense investigation. Work over the last decade has revealed not only a general protein chaperone role for Hsp90, but also a specific chaperone role in the binding of select conformations or metastable forms of signaling proteins (clients), thereby attenuating their signaling activity (4-6). Client proteins include the targets of key cancer survival and proliferation pathways, including Akt, Bcr-Abl, Her-2, mutant EGFR, and c-Kit, many of which are the subject of individual investigation for points of therapeutic intervention. Therefore, two functions of Hsp90 exist: (i) a general protein chaperone function (protein homeostasis) and (ii) a specific function to modulate the integrity of cell-signaling pathways through the proper folding of pathway members that are Hsp90 clients.Multiple myeloma (MM) is a neoplasm of terminally differentiated B cells (plasma cells) (7). Because of the high protein secr...

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Section: Ipi-504 and 17-aag Interconvert In Vitro And In Vivomentioning

confidence: 74%

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Sydor

Normant

Pien

et al. 2006

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

220

160

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“…None of the quinones tested showed decreased mutagenicity when DT-diaphorase was selectively inhibited with dicoumarol, thus indicating that the two-electron reduction pathway does not contribute to the mutagenic activation of these four quinones. This is in contrast to quinones possessing reactive leaving groups that have been shown to be converted to mutagens by DT-diaphorase (18)(19)(20). In the case of the naphthoquinone menadione, the mutagenicity was increased by the inhibition of DT-diaphorase.…”

Section: Discussionmentioning

confidence: 87%

“…To limit the scope of this project we also chose not to study quinones that possess reactive leaving groups. Quinones of this type have been shown to interact with DNA via a methide reaction (18)(19)(20).…”

mentioning

confidence: 99%

Mutagenicity of quinones: pathways of metabolic activation and detoxification.

Chesis¹,

Levin²,

Smith³

et al. 1984

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

319

132

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The mutagenicity of various quinones, a class of compounds widely distributed in nature, is demonstrated in the Salmonella TA104 tester strain. The metabolic pathways by which four quinones, menadione, benzo[alpyrene 3,6-quinone, 9,10-phenanthrenequinone, and danthron, caused mutagenicity in this test system were investigated in detail as were the detoxification pathways. The two-electron reduction of these quinones by NAD(P)H-quinone oxidoreductase (DT-diaphorase) was not mutagenic, whereas the one-electron reduction, catalyzed by NADPH-cytochrome P-450 reductase, was mutagenic, except for danthron, which was only slightly mutagenic. The mutagenicity of the quinones via this pathway was found to be attributable to the generation of oxygen radicals. The cytochrome P-450 monooxygenase also played a significant role in the detoxification and bioactivation of these quinones. For example, phenanthrenequinone was converted to a nonmutagenic metabolite in a cytochrome P-450-dependent reaction, whereas danthron was converted to a highly mutagenic metabolite. These studies show the complexity of metabolic pathways involved in the mutagenicity of quinones.Quinones are widely distributed in nature, and human exposure to them is extensive. The quinones of polycyclic aromatic hydrocarbons are abundant in all burnt organic material, including automobile exhaust, cigarette smoke, and urban air particulates (1-3). Quinones are also found naturally in many of the foods we eat (4-6), and compounds containing the quinone nucleus are widely employed as antitumor agents (7, 8). Despite the magnitude of this human exposure, the pathways by which many quinones are metabolized remain poorly understood and their mutagenicity is largely untested. In a recent study, however, six naturally occurring naphthoquinones, including menadione, were shown to be mutagenic to strain TA2637 with metabolic activation (9), indicating the need for further studies.Quinones serve as substrates for a wide variety of flavoenzymes, including NADPH-cytochrome P-450 reductase, NAD(P)H-quinone oxidoreductase (DT-diaphorase), NADHcytochrome b5 reductase, and NADH-ubiquinone oxidoreductase, and can undergo either a direct two-electron reduction to the hydroquinone or a one-electron reduction to the semiquinone radical (10-13). In the presence of oxygen most semiquinones rapidly autooxidize to form the superoxide anion radical (02.) and thus regenerate the quinone (14). This redox cycling can lead to conditions of oxidative stress through the production of 02 (15) and has been invoked to explain the cytotoxic and antitumor properties of quinonoid drugs (16). We have recently demonstrated that the xanthine oxidase-dependent superoxide-generating system is mutagenic to the new Salmonella tester strain TA104 (unpublished). This finding suggested that the redox cycling of quinones might also be mutagenic, and we have tested this possibility using the TA104 strain, which is sensitive to a wide variety of oxidative mutagens (17). We have also attempted to chara...

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“…Metabolism of doxorubicin by rat liver QAO has been reported (Komiyama et al, 1979) and it has been thought to be responsible for the covalent binding of doxorubicin to DNA catalyzed by rat liver cytosol and NADPH (Sinha and Gregory, 1981). QAO can also lead to the bioactivation of some cytotoxic halogenated dimethylnaphthoquinones (Berger et al, 1985;Talcott et al, 1983). In this scenario, increased QAO activity would make tumor tissue more susceptible than normal tissue to anti-tumor quinones, while decreased levels of tumor QAO, as in smokers, might decrease the effectiveness of chemotherapy with anti-tumor quinones.…”

Section: Discussionmentioning

confidence: 99%

“…Quinone anticancer drugs can be activated to alkylating species by reduction to the hydroquinone (Fisher et al, 1985;Gutierrez et al, 1986;Moore, 1977;Peterson and Fisher, 1986). Metabolism by QAO has been thought to be responsible for the formation of alkylating species from doxorubicin (Sinha and Gregory, 198 1) and other cytotoxic quinones (Berger et al, 1985;Talcott et al, 1983). The QAO inhibitor dicumarol increases the cytotoxicity of mitomycin C to hypoxic cells and decreases the cytotoxicity to euoxic cells (Keyes et al, 1984(Keyes et al, , 1986.…”

Section: Nad(p)h:(quinone-acceptor)oxidoreductase (Qao Ecmentioning

confidence: 99%

Cytosolic NAD(P)H:(Quinone‐acceptor)oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol

Schlager

Powis

1990

Intl Journal of Cancer

226

159

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NAD(P)H:(quinone-acceptor)oxidoreductase (QAO), previously known as DT-diaphorase, catalyzes the reduction of quinones to hydroquinones. Enhanced activity of the enzyme has been suggested to protect cells against the cellular toxicity and carcinogenicity of quinones, but may activate some cytotoxic anti-tumor quinones. Cytosolic levels of QAO, carbonyl reductase (CR) and total quinone reductase activity have been measured in normal and tumorous human tissues. QAO was the major component of the total cytosolic quinone reductase activity in all the tissues investigated. CR represented 10 to 28% of the total cytosolic quinone reductase activity in normal tissue. Normal tissue QAO was high in the stomach and kidney, and lower in the lung, liver, colon and breast. Primary tumor from lung, liver, colon and breast had elevated levels of QAO compared to normal tissue, while tumor from kidney and stomach had lower levels. CR was not significantly altered in tumor tissue, except in the case of lung and colon tumor which showed an increase compared to normal tissue. A major determinant of the variability of human lung tumor QAO was the cigarette-smoking history of the donor. Non-smokers and past smokers had high levels of tumor QAO compared to normal tissue. Smokers had levels of tumor QAO that were not significantly different from those of normal tissue QAO. Smokers had a small increase in normal lung QAO compared to non-smokers. Alcohol use was associated with an increase in lung tumor QAO but had no effect on QAO in normal lung. The function of QAO in tumors is not known but the elevated activity of QAO in some tumors and the apparent depressant effect of smoking could influence the response of these tumors to quinone drugs or toxic agents that are metabolized by QAO.

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Possible role of DT-diaphorase in the bioactivation of antitumor quinones

Cited by 37 publications

References 4 publications

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

Mutagenicity of quinones: pathways of metabolic activation and detoxification.

Cytosolic NAD(P)H:(Quinone‐acceptor)oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol

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