Related Experiment Videos
The role of glucuronidation in 7-ethyl-10-hydroxycamptothecin resistance in vitro
T Takahashi1, Y Fujiwara, M Yamakido
1Second Department of Internal Medicine, Hiroshima University School of Medicine.
Abstract:
Although glucuronidation catalyzed by uridine 5'-diphosphoglucuronosyltransferase (UGT) is a major pathway of drug inactivation in humans, glucuronidation in malignant cells has received little attention as a cause of anti-cancer drug resistance. In this study, we tried to elucidate the role of SN-38 glucuronidation in the CPT-11-resistant human lung cancer cell line PC-7/CPT. PC-7/CPT cells possessed an increased activity to glucuronidate SN-38 compared to the parent cells, PC-7. Furthermore, sensitivity of PC-7/CPT cells to SN-38 was improved by inhibiting UGT activity. Western and northern blot analyses demonstrated that this increased activity was due to increased levels of UGT protein and mRNA. These results not only imply that upregulation of UGT activity in PC-7/CPT cells may contribute in part to SN-38 resistance, but also illustrate the important of drug metabolism within malignant cells themselves, as a cause of drug resistance.
Insights
Cancer cells can resist chemotherapy by increasing uridine 5'-diphosphoglucuronosyltransferase (UGT) activity, which inactivates anti-cancer drugs like SN-38. This highlights drug metabolism
Area of Science:
- Pharmacology and Toxicology
- Cancer Biology
- Drug Metabolism
Background:
- Glucuronidation by uridine 5 -diphosphoglucuronosyltransferase (UGT) is a primary mechanism for drug inactivation in humans.
- The role of glucuronidation in mediating anti-cancer drug resistance within malignant cells remains underexplored.
Purpose of the Study:
- To investigate the significance of SN-38 glucuronidation in a CPT-11-resistant human lung cancer cell line (PC-7/CPT).
- To determine if enhanced UGT activity contributes to resistance against SN-38, a metabolite of irinotecan (CPT-11).
Main Methods:
- Comparison of SN-38 glucuronidation activity between drug-resistant (PC-7/CPT) and parent (PC-7) human lung cancer cells.
- Assessment of PC-7/CPT cell sensitivity to SN-38 following inhibition of UGT activity.
- Analysis of UGT protein and mRNA expression levels using Western and Northern blot techniques.
Main Results:
- PC-7/CPT cells exhibited significantly higher SN-38 glucuronidation activity compared to PC-7 cells.
- Inhibition of UGT activity in PC-7/CPT cells restored sensitivity to SN-38.
- Increased UGT protein and mRNA levels were observed in PC-7/CPT cells, correlating with enhanced glucuronidation activity.
Conclusions:
- Upregulation of UGT activity in PC-7/CPT cells is a contributing factor to SN-38 resistance.
- Drug metabolism within cancer cells themselves plays a crucial role in the development of anti-cancer drug resistance.
- Targeting drug-metabolizing enzymes like UGTs may offer novel strategies for overcoming chemotherapy resistance.