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Mithramycin represses MDR1 gene expression in vitro, modulating multidrug resistance
M Tagashira1, T Kitagawa, S Isonishi
1Foods and Pharmaceuticals Research and Development Laboratory, Asahi Breweries Ltd., Ibaraki, Japan. motoyuki.tagashira@asahibeer.co.jp
Biological & Pharmaceutical Bulletin
|August 30, 2000
Summary
Mithramycin (MTM) represses multidrug resistance (MDR) gene transcription and depletes P-glycoprotein (Pgp) in cancer cells. This aureolic acid sensitizes cells to chemotherapy, suggesting its potential as an MDR modulator.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
- P-glycoprotein (Pgp) is a key transporter involved in MDR.
- Targeting Pgp or its associated pathways is crucial for overcoming MDR.
Purpose of the Study:
- To investigate the effect of mithramycin (MTM), an aureolic acid, on multidrug resistance (MDR).
- To determine if MTM can modulate Pgp expression and function in MDR cancer cells.
- To assess MTM's potential to resensitize MDR cells to chemotherapy.
Main Methods:
- Cell culture of SBC-3/ADM, a multidrug-resistant human small cell lung tumor subline.
- Treatment with mithramycin (MTM) at varying concentrations (0.02–0.1 mg/ml).
- Flow cytometry (FACS) analysis to assess P-glycoprotein (Pgp) levels and efflux activity.
- Assessment of cell sensitization to adriamycin.
Main Results:
- MTM repressed MDR1 gene transcription in SBC-3/ADM cells.
- MTM (5 µM) depleted Pgp and reduced drug efflux activity.
- MTM sensitized SBC-3/ADM cells to adriamycin treatment.
- Chromomycin A3, another aureolic acid, exhibited potent cytotoxicity under similar conditions.
Conclusions:
- Mithramycin (MTM) effectively inhibits MDR1 gene transcription.
- MTM reduces Pgp expression and function, thereby overcoming MDR.
- MTM shows promise as a modulator to enhance chemotherapy efficacy in Pgp-mediated MDR cancers.