Preclinical Evaluation of the Pharmacodynamic Properties of 2,5-Diaziridinyl-3-Hydroxymethyl-6-Methyl-1,4-Benzoquinone

Ward, Timothy H; Danson, Sarah; McGown, Alan T.; Ranson, Malcolm R; Coe, Nicholas A.; Jayson, Gordon C; Cummings, Jeffrey L.; Hargreaves, Robert H J; Butler, J. A. V.

doi:10.1158/1078-0432.ccr-04-1751

Cited by 24 publications

(17 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reduction of RH1 activates aziridine residues, which subsequently induce DNA damage (Cummings et al, 2003;Kim et al, 2004a;Kim et al, 2004b;Ward et al, 2005;Hussein et al, 2009). Because NQO1 is abundantly expressed in a variety of cancer tissues, it has been suggested that such tissues can be selectively damaged by RH1.…”

Section: Discussionmentioning

confidence: 99%

“…Because NQO1 is abundantly expressed in a variety of cancer tissues, it has been suggested that such tissues can be selectively damaged by RH1. This enzymedirected cancer-targeting agent is currently being tested in clinical trials (Cummings et al, 2003;Kim et al, 2004a;Kim et al, 2004b;Ward et al, 2005;Hussein et al, 2009). However, the molecular mechanisms underlying the therapeutic effects of the agent on solid tumours have not yet been clearly elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The anti-cancer activity of RH1 has been attributed to two-electron reduction by NAD(P)H quinone oxidoreductase 1 (NQO1, DTdiaphorase), an enzyme abundantly expressed in a variety of human solid tumours, including those of the breast, pancreas, lung and colon (Cummings et al, 2003;Kim et al, 2004a). NQO1-mediated reduction of RH1 results in activation of the aziridine rings, in turn inducing DNA alkylation and crosslinking (Cummings et al, 2003;Kim et al, 2004a;Kim et al, 2004b;Ward et al, 2005;Hussein et al, 2009). Several lines of evidence indicate that NQO1 positively regulates p53 stability by inhibiting p53 degradation (Asher et al, 2001;Nioi and Hayes, 2004).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

Park¹,

Song²,

Oh³

et al. 2011

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSE2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although the cytotoxic efficacy of RH1 against tumours has been studied extensively, the molecular mechanisms underlying this anti-cancer activity have not yet been fully elucidated. EXPERIMENTAL APPROACH2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone-induced apoptosis and related signalling pathways in NQO1-negative and NQO1-overexpressing cells were evaluated. The role of p53 in RH1-induced cell death was investigated using parental and p53-deficient RKO human colorectal cancer cells by assaying clonogenic cell survival. Specific inhibitors and siRNAs targeting factors involved in RH1-induced apoptosis were used to clarify the roles played by such factors in RH1-activated apoptotic signalling pathways. KEY RESULTS2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone induced apoptosis and clonogenic death, dependent on NQO1 and p53. Treatment of NQO1-overexpressing cells with RH1 caused rapid disruption of mitochondrial membrane potential, nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G) from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNA targeting AIF and Endo G effectively attenuated RH1-induced apoptotic cell death. Moreover, RH1 induced cleavage of Bax, which targets mitochondria. RH1 significantly activated the c-Jun N-terminal kinase (JNK) pathway, and inhibition of this pathway suppressed RH1-induced mitochondria-mediated apoptosis. RH1-induced generation and mitochondrial translocation of cleaved Bax were blocked by the JNK inhibitor, SP600125. Inhibition of JNK with SP600125 attenuated the mitochondrial translocation of JNK. CONCLUSIONS AND IMPLICATIONS2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone activated JNK, resulting in mitochondria-mediated apoptotic cell death that was NQO1-dependent. AbbreviationsAIF, apoptosis-inducing factor; DiOC6(3), 3

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

Park¹,

Song²,

Oh³

et al. 2011

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…RH1 is a compound selected for clinical development by the Cancer Research Campaign (CRC) and the NCI, and after its preclinical evaluation [15], it successfully underwent phase 1 evaluation [16].…”

Section: Introductionmentioning

confidence: 99%

NAD(P)H:Quinone Oxidoreductase 1 Expression in Human Primary Melanotic Melanomas of the Skin

Zappa¹

2014

J Cytol Histol

View full text Add to dashboard Cite

NAD(P)H:quinone oxidoreductase 1 (NQ01; DT-diaphorase; DTD) is a two-electron reducing enzyme which is often over-expressed in cancers and can activate quinones to form cytotoxic species. This over-expression is used as target in the design of novel anti-cancer drugs. DTD is also expressed in normal tissues, but little is known about its "body mapping". Because of the dearth of information on the cell-specific expression of DTD in pigmentproducing cells of the skin, we analysed its expression in normal and tumoral samples. Twenty skin biopsies of primary malignant melanotic melanomas (ten with vertical invasion, ten with superficial spreading) were analysed by immunohistochemistry. In normal skin DTD expression was weak in all epidermal layers, including normal melanocytes. Malignant melanomas showed a very strong DTD expression in tumoral cells of all samples and in endothelial lining of peri-tumoral vessels.These results suggest that DT-diaphorase may be a new marker that could be useful in determining the extent of a malignant melanocytic lesion, and also tend to support the potential of malignant melanomas as target for DTDdirected antitumour agents.

show abstract

“…These compounds are activatable by the enzyme NQO1, which is rarely expressed in most normal human tissues but is highly upregulated in many tumor cells. RH1 (compound 3), AZQ (compound 4), and TZQ (compound 5) have been shown to be effective anticancer agents in preclinical studies, with RH1 recently completing phase I trials (4,14,61). All appear to induce cell damage primarily by DNA alkylation and cross-linking following reductive activation (13,66).…”

mentioning

confidence: 99%

Targeting the Substrate Preference of a Type I Nitroreductase To Develop Antitrypanosomal Quinone-Based Prodrugs

Hall

Meredith

Wilkinson

2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Nitroheterocyclic prodrugs are used to treat infections caused by Trypanosoma cruzi and Trypanosoma brucei. A key component in selectivity involves a specific activation step mediated by a protein homologous with type I nitroreductases, enzymes found predominantly in prokaryotes. Using data from determinations based on flavin cofactor, oxygen-insensitive activity, substrate range, and inhibition profiles, we demonstrate that NTRs from T. cruzi and T. brucei display many characteristics of their bacterial counterparts. Intriguingly, both enzymes preferentially use NADH and quinones as the electron donor and acceptor, respectively, suggesting that they may function as NADH:ubiquinone oxidoreductases in the parasite mitochondrion. We exploited this preference to determine the trypanocidal activity of a library of aziridinyl benzoquinones against bloodstream-form T. brucei. Biochemical screens using recombinant NTR demonstrated that several quinones were effective substrates for the parasite enzyme, having K cat /K m values 2 orders of magnitude greater than those of nifurtimox and benznidazole. In tests against T. brucei, antiparasitic activity mirrored the biochemical data, with the most potent compounds generally being preferred enzyme substrates. Trypanocidal activity was shown to be NTR dependent, as parasites with elevated levels of this enzyme were hypersensitive to the aziridinyl agent. By unraveling the biochemical characteristics exhibited by the trypanosomal NTRs, we have shown that quinone-based compounds represent a class of trypanocidal compound.

show abstract

Preclinical Evaluation of the Pharmacodynamic Properties of 2,5-Diaziridinyl-3-Hydroxymethyl-6-Methyl-1,4-Benzoquinone

Cited by 24 publications

References 40 publications

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

NAD(P)H:Quinone Oxidoreductase 1 Expression in Human Primary Melanotic Melanomas of the Skin

Targeting the Substrate Preference of a Type I Nitroreductase To Develop Antitrypanosomal Quinone-Based Prodrugs

Contact Info

Product

Resources

About