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Role of P-glycoprotein in dolastatin 10 resistance
D L Toppmeyer1, C A Slapak, J Croop
1Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
Abstract:
Dolastatin 10, a cytotoxic pentapeptide isolated from the mollusk Dolabella auricularia, exhibits potent antitumor activity. The present studies demonstrated that sublines of murine PC4 and human U-937 leukemia cells expressing a multidrug resistance (MDR) phenotype are cross-resistant to this agent. We also demonstrated that such resistance was reversed by verapamil. While these findings suggested the involvement of the P-glycoprotein (P-gp) in dolastatin 10 resistance, we performed similar studies in a CHO cell line transfected with the human mdr1 cDNA. Expression of P-gp in the transfected cells was associated with resistance to dolastatin 10 by a verapamil-sensitive mechanism. The demonstration that photoaffinity labeling of P-gp was decreased in the presence of dolastatin 10 further supports the interaction of this cytotoxic peptide with P-gp. Taken together, these findings suggest that resistance to dolastatin 10 is conferred, at least in part, by P-gp and that this cytotoxic peptide is a novel member of the MDR phenotype.
Insights
Dolastatin 10, an antitumor peptide, shows cross-resistance in multidrug resistance (MDR) cells. This resistance is reversed by verapamil and linked to P-glycoprotein (P-gp) interaction.
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- Dolastatin 10, a cytotoxic pentapeptide from Dolabella auricularia, possesses potent antitumor properties.
- Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy, limiting the efficacy of cytotoxic agents.
- P-glycoprotein (P-gp) is a key efflux pump implicated in MDR.
Purpose of the Study:
- To investigate the mechanism of resistance to Dolastatin 10 in cancer cells.
- To determine the role of P-glycoprotein (P-gp) in mediating resistance to Dolastatin 10.
- To explore the potential of verapamil in reversing Dolastatin 10 resistance.
Main Methods:
- Utilized murine PC4 and human U-937 leukemia cell lines exhibiting MDR phenotype.
- Employed a Chinese hamster ovary (CHO) cell line transfected with human mdr1 cDNA to study P-gp function.
- Assessed Dolastatin 10 resistance and its reversal by verapamil.
- Performed photoaffinity labeling of P-gp in the presence of Dolastatin 10.
Main Results:
- Murine PC4 and human U-937 leukemia cells with MDR phenotype demonstrated cross-resistance to Dolastatin 10.
- Verapamil effectively reversed the observed resistance to Dolastatin 10.
- CHO cells transfected with human mdr1 cDNA expressing P-gp showed verapamil-sensitive resistance to Dolastatin 10.
- Photoaffinity labeling indicated a decreased interaction with P-gp in the presence of Dolastatin 10.
Conclusions:
- P-glycoprotein (P-gp) confers, at least partially, resistance to Dolastatin 10.
- Dolastatin 10 is identified as a novel agent associated with the multidrug resistance (MDR) phenotype.
- These findings suggest potential strategies for overcoming Dolastatin 10 resistance in cancer therapy.