From the Guidelines
The likely mechanism of resistance in this cancer cell clone is overexpression of P-glycoprotein (P-gp), also known as multidrug resistance protein 1 (MDR1). This conclusion is based on the pattern of drug resistance observed, where the cells are resistant to vincristine, doxorubicin, and dactinomycin but sensitive to methotrexate and alkylating agents, as described in the context of multiple drug resistance (MDR) 1. The role of extracellular vesicles (EVs), including small EVs (sEVs) like exosomes, in modulating chemoresistance by transmitting molecular information between cells, is an area of active research 1. However, the specific pattern of resistance to drugs that are known substrates for P-glycoprotein, such as vincristine, doxorubicin, and dactinomycin, points towards P-gp overexpression as the primary mechanism.
Key points to consider include:
- P-glycoprotein functions as a transmembrane efflux pump, reducing the intracellular concentration of its substrate drugs by actively pumping them out of the cell.
- The drugs to which the cancer cells are resistant (vincristine, doxorubicin, and dactinomycin) are all substrates for P-glycoprotein, explaining the observed resistance.
- Methotrexate and alkylating agents, to which the cells remain sensitive, are not efficiently transported by P-gp, consistent with the MDR phenotype.
- Understanding this mechanism is crucial for developing strategies to overcome resistance, such as using P-gp inhibitors or selecting alternative chemotherapeutic agents not affected by P-gp efflux 1.
Given the most recent evidence from 2022 1, the focus on P-glycoprotein overexpression as the mechanism of resistance aligns with contemporary understanding of MDR in cancer cells, highlighting the importance of considering efflux pump activity in the development of chemoresistance.
From the Research
Mechanism of Resistance
The mechanism of resistance in a clone of cancer cells that is resistant to vincristine, doxorubicin, and dactinomycin but sensitive to methotrexate and alkylating agents is most likely to involve:
- Overexpression of P-glycoprotein, a cell surface glycoprotein that acts as an energy-dependent drug efflux pump, reducing the intracellular concentration of structurally unrelated drugs 2, 3
- Multidrug resistance (MDR) phenotype, which is characterized by cross-resistance to multiple anticancer agents, including inhibitors of topoisomerase II and microtubule poisons 3, 4
Evidence for P-glycoprotein Overexpression
Studies have shown that P-glycoprotein overexpression is associated with resistance to doxorubicin, vincristine, and other anticancer agents 2, 3, 5, 6
- Western blotting and immunohistochemistry have been used to detect P-glycoprotein overexpression in resistant cells 3, 6
- P-glycoprotein expression has been observed in tumor cells and vascular endothelial cells, suggesting a role in drug resistance 5
Alternative Mechanisms
Alternative mechanisms of resistance, such as altered drug efflux or differential drug binding, may also be involved in some cases 3
- Studies have shown that some resistant cells do not overexpress P-glycoprotein, suggesting that other mechanisms may be responsible for resistance 3, 4
Reversal of Resistance
Reversal of P-glycoprotein-mediated multidrug resistance has been achieved using modulators of P-glycoprotein function, such as diallyl sulfide 6
- Diallyl sulfide has been shown to decrease P-glycoprotein levels and enhance the cytotoxic effects of vinca alkaloids in resistant cells 6