Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase

Abstract

Summary DT-diaphorase is a two-electron reducing enzyme that activates the bioreductive anti-tumour agent, mitomycin C (MMC). Cell lines having elevated levels of DT-diaphorase are generally more sensitive to MMC. We have shown that DT-diaphorase can be induced in human tumour cells by a number of compounds, including 1,2-dithiole-3-thione. In this study, we investigated whether induction of DT-diaphorase could enhance the cytotoxic activity of MMC in six human tumour cell lines representing four tumour types. DT-diaphorase was induced by many dietary inducers, including propyl gallate, dimethyl maleate, dimethyl fumarate and sulforaphane. The cytotoxicity of MMC was significantly increased in four tumour lines with the increase ranging from 1.4-to threefold. In contrast, MMC activity was not increased in SK-MEL-28 human melanoma cells and AGS human gastric cancer cells, cell lines that have high base levels of DT-diaphorase activity. Toxicity to normal human marrow cells was increased by 50% when MMC was combined with 1,2-dithiole-3-thione, but this increase was small in comparison with the threefold increase in cytotoxicity to tumour cells. This study demonstrates that induction of DT-diaphorase can increase the cytotoxic activity of MMC in human tumour cell lines, and suggests that it may be possible to use non-toxic inducers of DT-diaphorase to enhance the efficacy of bioreductive anti-tumour agents.

Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo

“…Treatment of HCT116 cells in vitro with DMF for 48 h increased NQO1 activity in these cells by two-fold (Po0.001), and cells that were pretreated with DMF were 1.4-fold more sensitive to MMC than cells that were not pretreated (Po0.001). This result was similar to our previous findings in murine lymphoma cells (Begleiter et al, 1996) and human breast, lung and colon cancer cells (Doherty et al, 1998;Wang et al, 1999) using synthetic inducers of NQO1.…”

“…Cells with elevated NQO1 levels are generally more sensitive to MMC (Begleiter et al, 1989;Marshall et al, 1989;Siegel et al, 1990), and NQO1 can be induced by a wide variety of dietary and synthetic agents (Talalay et al, 1988;Prestera et al, 1993). We have previously shown that NQO1 activity can be selectively increased in tumour cells compared with normal cells, and that this enhances MMC cytotoxicity in human and murine cell lines in vitro (Doherty et al, 1998;Wang et al, 1999). In this study we investigated a novel approach to increasing the antitumour activity of MMC by using a dietary component to selectively induce NQO1 activity in tumour cells compared with normal cells.…”

“…Thus, selectively increasing the level of NQO1 in tumour cells by gene transfer (Rauth et al, 1998) or by selective induction of NQO1 in tumours may be useful for enhancing the efficacy of bioreductive agents. We showed previously that we could selectively increase NQO1 activity in tumour cells compared with normal cells and that this enhanced MMC antitumour activity in vitro (Doherty et al, 1998;Wang et al, 1999). In this study we investigated whether we could selectively induce NQO1 activity in human tumours implanted in a nude mouse model, and if this would increase the antitumour activity of bioreductive agents without increasing the toxicity of these agents.…”

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

“…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.…”

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

“…We propose the following mechanisms that might explain this individual susceptibility to MMC-related renal toxicity. (a) DT-diaphorase can be induced by a wide variety of compounds, including many dietary substances (Benson et al 1980;O'Dwyer et al 1996;Begleiter et al 1997;Wang et al 1999). For example, rapid induction of this enzyme has been demonstrated in subjects who regularly ingest coffee or broccoli (Sreerama et al 1995).…”