Increased sensitivity of quinone resistant cells to mitomycin C
A Begleiter1, E Robotham, G Lacey
1Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Cancer Letters
|June 1, 1989
Summary
Quinone-resistant cells showed increased sensitivity to mitomycin C, suggesting DNA cross-linking is key. DT-diaphorase activity and its inhibition by dicoumarol influenced this response.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Quinone-based chemotherapy agents are vital in cancer treatment.
- Understanding drug resistance mechanisms is crucial for improving therapeutic efficacy.
- L5178Y cells resistant to hydrolyzed benzoquinone mustard provide a model for studying quinone drug resistance.
Purpose of the Study:
- To investigate the sensitivity of quinone-resistant L5178Y cells to mitomycin C.
- To elucidate the role of DT-diaphorase activity in mitomycin C cytotoxicity and DNA cross-linking.
- To explore the potential contribution of DNA cross-linking to mitomycin C's anticancer effects.
Main Methods:
- Comparative sensitivity assays of mitomycin C in parental and quinone-resistant L5178Y cells.
- Assessment of DNA-DNA cross-linking and DNA double-strand breaks induced by mitomycin C.
- Measurement of DT-diaphorase activity in both cell lines.
- Evaluation of dicoumarol's effect on mitomycin C's cytotoxicity and cross-linking in resistant cells.
Main Results:
- Quinone-resistant L5178Y cells exhibited a four-fold increased sensitivity to mitomycin C.
- Mitomycin C induced greater DNA-DNA cross-linking in resistant cells but no DNA double-strand breaks.
- Resistant cells displayed a 24-fold elevation in DT-diaphorase activity.
- Dicoumarol significantly reduced mitomycin C-induced cross-linking and cytotoxicity in resistant cells.
Conclusions:
- DNA-DNA cross-linking is a significant factor in mitomycin C's cytotoxic activity in L5178Y cells.
- The hydroquinone form of mitomycin C likely plays a major role in its DNA cross-linking capability.
- DT-diaphorase activity is implicated in the response of quinone-resistant cells to mitomycin C.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
02:56Treatment Resistant Cancers
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...