Quinone-induced apoptosis in human colon adenocarcinoma cells via DT-diaphorase mediated bioactivation
1School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA.
Abstract:
DT-diaphorase (DTD) activity has been related to bioactivation and cytotoxicity of antitumor quinones. A pair of human colon adenocarcinoma cell lines, HT29 and BE, were used in this study to examine the role of DTD in antitumor quinone induced apoptosis. HT29 cells have elevated levels of DTD whereas BE cells lack functional DTD due to a point mutation which results in a complete lack of DTD activity. MeDZQ, a quinone that is efficiently bioactivated by DTD, induced apoptosis both in HT29 and BE cells, but with a much higher incidence in HT29, as assessed by morphological criteria and the formation of oligonucleosomal fragments of DNA. Two other quinone compounds which are also substrates for DTD, i.e. streptonigrin and mitomycin C, also preferentially induced apoptosis in HT29 cells, which could be inhibited by dicoumarol. Our data suggest that bioreductive activation of antitumor quinones by DTD results in induction of apoptosis in human colon carcinoma cells.
Insights
DT-diaphorase (DTD) plays a key role in activating antitumor quinones. This enzyme significantly enhances quinone-induced apoptosis in human colon cancer cells, offering a potential therapeutic target.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- DT-diaphorase (DTD) is implicated in the bioactivation and cytotoxicity of antitumor quinones.
- Understanding DTD's role in apoptosis is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the role of DT-diaphorase (DTD) in mediating apoptosis induced by antitumor quinones in human colon adenocarcinoma cell lines.
- To compare the effects of DTD-dependent quinones on cell lines with varying levels of DTD activity.
Main Methods:
- Utilized two human colon adenocarcinoma cell lines: HT29 (elevated DTD) and BE (lacking functional DTD).
- Assessed apoptosis using morphological criteria and DNA fragmentation (oligonucleosomal fragments).
- Investigated the effects of MeDZQ, streptonigrin, and mitomycin C, and the impact of the DTD inhibitor dicoumarol.
Main Results:
- MeDZQ, a DTD substrate, induced apoptosis in both HT29 and BE cells, but with significantly higher incidence in DTD-rich HT29 cells.
- Other DTD substrates, streptonigrin and mitomycin C, also preferentially induced apoptosis in HT29 cells.
- Dicoumarol inhibited the quinone-induced apoptosis, confirming DTD's involvement.
Conclusions:
- Bioreductive activation of antitumor quinones by DT-diaphorase (DTD) is a key mechanism for inducing apoptosis in human colon carcinoma cells.
- DTD activity levels directly correlate with the efficacy of certain quinone-based chemotherapeutics.
- Targeting DTD could enhance the therapeutic potential of quinone-based anticancer drugs.
