Related Experiment Videos
P-glycoprotein mediates profound resistance to bisantrene
X P Zhang1, M K Ritke, J C Yalowich
1Oncology and Immunology Research Section, Lederle Laboratories, Division of American Cyanamid, Pearl River, NY 10965.
Abstract:
Bisantrene, mitoxantrone, and anthracyclines are anthracene derivatives that interact with DNA and are used for the treatment of cancers. The mechanisms of resistance to bisantrene are unknown. Here we show that cells that overexpress low levels of P-glycoprotein or are transfected with human MDR1 have approximately 10-fold greater resistance to bisantrene compared to vinblastine, doxorubicin, or colchicine. Furthermore, bisantrene can be used to select for high-level P-glycoprotein-mediated multiple drug resistance in a human colon carcinoma cell line, LS 174T, and the drug blocks photoaffinity labeling of P-glycoprotein. The data suggest that bisantrene is an excellent substrate for P-glycoprotein. These findings could influence subsequent clinical evaluation of bisantrene for the treatment of cancer.
Insights
Bisantrene resistance in cancer cells is linked to P-glycoprotein (P-gp). Overexpressing P-gp increases resistance, suggesting P-gp is a key factor in bisantrene
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Bisantrene, mitoxantrone, and anthracyclines are DNA-interacting anthracene derivatives used in cancer therapy.
- The mechanisms underlying resistance to bisantrene are not well understood.
Purpose of the Study:
- To investigate the mechanisms of resistance to bisantrene.
- To determine if P-glycoprotein (P-gp) plays a role in bisantrene resistance.
Main Methods:
- Transfecting cells with human MDR1 gene to overexpress P-gp.
- Comparing bisantrene resistance in cells with varying P-gp levels.
- Using bisantrene to select for multidrug-resistant cell lines.
- Photoaffinity labeling of P-glycoprotein.
Main Results:
- Cells overexpressing P-gp or MDR1 showed approximately 10-fold greater resistance to bisantrene.
- Bisantrene effectively selected for high-level P-gp-mediated multidrug resistance in LS 174T colon carcinoma cells.
- Bisantrene was found to block photoaffinity labeling of P-gp, indicating it is a substrate.
Conclusions:
- Bisantrene is an excellent substrate for P-glycoprotein.
- P-glycoprotein-mediated efflux is a significant mechanism of resistance to bisantrene.
- These findings may impact the clinical use of bisantrene in cancer treatment.