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Does any relationship exist between P-glycoprotein-mediated multidrug resistance and intracellular calcium
Zdenka Sulová1, Mário Seres, Miroslav Barancík
1Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Centre of Excellence of the Slovak Research and Development Agency BIOMEMBRANES2008, 833 34 Bratislava, Slovakia.
Abstract:
Multidrug resistance (MDR) of neoplastic tissue represents a real obstacle to the effective chemotherapy of cancer. Several mechanisms of MDR were identified, from which the over-expression and efflux activity of P-glycoprotein (P-gp) - a plasma membrane ATPase (ABCB1 member of ABC transporter family) - represents the most commonly observed reason for neoplastic disease chemotherapy malfunction. The process of P-gp-mediated MDR seems to be related to intracellular calcium homeostasis, at least indirectly, for the following reasons: i. substances blocking calcium influx through L-type of calcium channels like verapamil were often found to antagonize P-gp-mediated MDR; ii. calcium signal abnormalities were observed in cells over-expressing P-gp; iii. cells with P-gp-mediated MDR were often resistant to thapsigargin; iv. several differences in intracellular calcium localization were observed when P-gp-negative and P-gp-positive cells were compared; and v. differences in the contents of several proteins of the endoplasmic reticulum involved in calcium homeostasis were observed to be associated with P-gp over-expression. This current study represents an attempt to summarize the knowledge about the possible relationship between P-gp-mediated MRD and intracellular calcium homeostasis.
Insights
Multidrug resistance (MDR) in cancer, often due to P-glycoprotein (P-gp), may be linked to intracellular calcium changes. This study explores the connection between P-gp-mediated MDR and calcium homeostasis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Multidrug resistance (MDR) in neoplastic tissues hinders effective cancer chemotherapy.
- P-glycoprotein (P-gp), a plasma membrane ATPase, is a primary cause of MDR due to its efflux activity.
- P-gp belongs to the ABC transporter family (ABCB1).
Purpose of the Study:
- To summarize existing knowledge on the relationship between P-gp-mediated MDR and intracellular calcium homeostasis.
- To investigate the indirect links between P-gp activity and cellular calcium regulation.
- To consolidate findings on how calcium signaling impacts chemotherapy resistance.
Main Methods:
- Review and synthesis of existing scientific literature.
- Analysis of studies investigating P-gp over-expression and its correlation with calcium signaling.
- Examination of evidence linking calcium channel blockers and MDR.
- Comparison of calcium localization and endoplasmic reticulum protein content in P-gp positive and negative cells.
Main Results:
- Substances blocking L-type calcium channels, like verapamil, can antagonize P-gp-mediated MDR.
- Abnormal calcium signaling is observed in cells over-expressing P-gp.
- Cells exhibiting P-gp-mediated MDR often show resistance to thapsigargin.
- Differences in intracellular calcium localization exist between P-gp-negative and P-gp-positive cells.
- Altered endoplasmic reticulum proteins involved in calcium homeostasis are associated with P-gp over-expression.
Conclusions:
- A potential relationship exists between P-gp-mediated multidrug resistance and intracellular calcium homeostasis.
- Modulation of calcium signaling pathways may offer strategies to overcome P-gp-driven chemotherapy resistance.
- Further research is warranted to fully elucidate the mechanisms connecting P-gp and calcium regulation in cancer.
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