Complete reversal by thaliblastine of 490-fold adriamycin resistance in multidrug-resistant (MDR) human breast cancer cells. Evidence that multiple biochemical changes in MDR cells need not correspond to multiple functional determinants for drug resistance. J Pharmacol Exp Ther 1995 Sep;274(3):1271-7
Date
09/01/1995Pubmed ID
7562498Scopus ID
2-s2.0-0029151639 (requires institutional sign-in at Scopus site) 18 CitationsAbstract
The emergence of drug resistance is a major obstacle to effective cancer chemotherapy. The identification of novel agents that serve as selective, potent and nontoxic modulators of drug resistance is thus an important goal for improving the success of cancer treatment. Thaliblastine (TBL), a plant alkaloid and P-glycoprotein (P-gp) inhibitor, is presently shown to fully reverse 490-fold resistance to Adriamycin (AdR) in a multidrug-resistant (MDR) human breast cancer cell line (MCF/AdR) that overexpresses P-gp, whereas the same treatment had no effect on AdR cytotoxicity in the drug-sensitive parental MCF-7 cells. Mechanistic studies showed that this striking resistance reversal was achieved without alteration of cellular levels of glutathione and without inhibition of glutathione S-transferase, glutathione peroxidase or P450 reductase by TBL, each of which is significantly altered in MCF/AdR cells, and each of which has been proposed to contribute to AdR resistance in this MDR line. Rather, resistance reversal by TBL can be entirely explained by this drug's capacity to restore the intracellular accumulation of AdR in the resistant cells. These results establish that MDR associated with P-gp overexpression can be fully reversed by the potent P-gp inhibitor TBL. They further indicate that although changes in multiple drug-metabolizing enzymes may accompany the development of MDR, these multiple biochemical alterations need not correspond to multiple functional determinants for drug resistance.
Author List
Chen G, Waxman DJAuthor
Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antibiotics, AntineoplasticAntineoplastic Agents, Phytogenic
Aporphines
Benzylisoquinolines
Breast Neoplasms
Doxorubicin
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Drug Synergism
Glutathione Peroxidase
Glutathione Transferase
Humans
Isoquinolines
NADPH-Ferrihemoprotein Reductase
Oxidoreductases
Tumor Cells, Cultured