Mechanisms of action of quinone-containing alkylating agents i: NQO1-directed drug development

Howard, D. Beall

doi:10.2741/beall

Cited by 42 publications

(16 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although only two N-unsubstituted indolequinones were investigated, both are good substrates for hNQO1 ( Table 1, [10][11][12][13][14][15][16][17][18][19][20][21]. This effect of an electron-withdrawing substituent at C-3 has been noted previously; cf.…”

Section: Resultsmentioning

confidence: 91%

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

et al. 2001

View full text Add to dashboard Cite

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1) were studied. Indolequinones were selected for study on the basis of the X-ray crystal structure of the human enzyme, and were designed to probe the effect of substituents particularly at N-1. Metabolism of the quinones by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, and that groups larger than methyl at N-1 are clearly tolerated. Compounds with a leaving group at the 3-indolyl methyl position generally inactivated the enzyme. The toxicity toward human colon carcinoma cells with either no detectable activity (BE-WT) or high NQO1 activity (BE-NQ) was also studied in representative quinones. The most toxic compounds were those with a leaving group at the C-3 position; these compounds were 1.1-5.3-fold more toxic to the BE-NQ than the BE-WT cells.

show abstract

Section: Resultsmentioning

confidence: 91%

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

et al. 2001

View full text Add to dashboard Cite

show abstract

“…The major drawback of quinone-based prodrugs is that they are often good substrates for oxygen-insensitive 2-electron reductases (20). CI-1010 did not proceed to clinical trials because of the irreversible retinal toxicity observed in preclinical testing (21).…”

Section: Introductionmentioning

confidence: 99%

Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer

Sun

Liu²,

Wang³

et al. 2012

Clinical Cancer Research

169

164

View full text Add to dashboard Cite

Purpose: Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, and metastatic cancer phenotype. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose of this study is to characterize the antitumor activity of TH-302 and investigate its selective targeting of the hypoxic cells in human tumor xenograft models.Experimental Design: Antitumor efficacy was assessed by tumor growth kinetics or by clonogenic survival of isolated cells after tumor excision. Hypoxic fractions (HF) were determined by immunohistochemistry and morphometrics of pimonidazole staining. Tumor hypoxia levels were manipulated by exposing animals to different oxygen concentration breathing conditions. The localization and kinetics of TH-302 induced DNA damage was determined by gH2AX immunohistochemistry.Results: TH-302 antitumor activity was dose-dependent and correlated with total drug exposure. Correlation was found between antitumor activity and tumor HF across 11 xenograft models. Tumorbearing animals breathing 95% O 2 exhibited attenuated TH-302 efficacy, with whereas those breathing 10% O 2 exhibited enhanced TH-302 efficacy, both compared with air (21% O 2 ) breathing. TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction. TH-302 induced DNA damage as measured by gH2AX was initially only present in the hypoxic regions and then radiated to the entire tumor in a time-dependent manner, consistent with TH-302 having a "bystander effect."Conclusions: The results show that TH-302 has broad antitumor activity and selectively targets hypoxic tumor tissues. Clin Cancer Res; 18(3); 758-70. Ó2011 AACR.

show abstract

“…Based on the known overexpression and increased specific enzymatic activity of NQO1 in various human tumors, NQO1-activated bioreductive alkylating agents including mitomycin C and other aziridinylquinones (EO9, diaziquone, RH1) have been developed as molecularly targeted anticancer chemotherapeutic prodrugs [42]. In analogy, PRC compounds may therefore represent a novel class of bioreductive experimental anti-cancer agents that eliminate cancer cells by NQO1-driven redox cycling with induction of apoptosis without imposing the burden of genotoxic alkylating stress observed with conventional bioreductive chemotherapeutic agents [52]. Interestingly, enhanced cytotoxicity of mitomycin C can be achieved in human tumor cells treated with small molecule inducers of NQO1 including sulforaphane and 1,2-dithiole-3-thione [53], and it remains to be seen if NQO1-induction by these classic chemopreventive inducers of phase II detoxification enzymes including NQO1 further sensitizes cancer cells to PRC-induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

Wondrak

2007

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Altered redox signaling and regulation in cancer cells represent a chemical vulnerability that can be targeted by selective chemotherapeutic intervention. Here, we demonstrate that 3,7-diaminophenothiazinium-based redoxcyclers (PRC) induce selective cancer cell apoptosis by NAD (P)H:quinone oxidoreductase (NQO1)-dependent bioreductive generation of cellular oxidative stress. Using PRC lead compounds including toluidine blue against human metastatic G361 melanoma cells, apoptosis occurred with phosphatidylserine-externalization, loss of mitochondrial transmembrane potential, cytochrome C release, caspase-3 activation, and massive ROS production. Consistent with reductive activation and subsequent redoxcycling as the mechanism of PRC cytotoxicity, co-incubation with catalase achieved cell protection, whereas reductive antioxidants enhanced PRC-cytotoxicity. Unexpectedly, human A375 melanoma cells were resistant to PRCinduced apoptosis, and PRC-sensitive G361 cells were protected by preincubation with the NQO1-inhibitor dicoumarol. Indeed, NQO1 specific enzymatic activity was nine fold higher in G361 than in A375 cells. The critical role of NQO1 in PRC-bioactivation and cytotoxicity was confirmed, when NQO1-transfected breast cancer cells (MCF7-DT15) stably overexpressing active NQO1 displayed strongly enhanced PRC-sensitivity as compared to vector-control transfected cells with base line NQO1 activity. Based on the known overexpression of NQO1 in various tumors these findings suggest the feasibility of developing PRC lead compounds into tumor-selective bioreductive chemotherapeutics.

show abstract

Mechanisms of action of quinone-containing alkylating agents i: NQO1-directed drug development

Cited by 42 publications

References 77 publications

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

Contact Info

Product

Resources

About