Multidrug Resistance Mechanisms in Chemotherapy
Primary Mechanism: P-glycoprotein (P-gp) Overexpression
The most common mechanism of multidrug resistance (MDR) in chemotherapy is overexpression of P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter encoded by the MDR1/ABCB1 gene, which functions as an efflux pump that actively expels chemotherapeutic drugs from cancer cells, thereby reducing intracellular drug concentrations below therapeutic levels. 1, 2
How P-glycoprotein Causes MDR
P-gp acts as a drug efflux pump that uses ATP hydrolysis to transport multiple structurally unrelated chemotherapeutic agents out of cancer cells, including anthracyclines (doxorubicin), taxanes, vinca alkaloids, and platinum-based agents 2, 3
Reduced intracellular drug accumulation occurs when P-gp is overexpressed, preventing chemotherapeutic agents from reaching cytotoxic concentrations necessary to induce cancer cell death 1, 4
The MDR1 gene overexpression can be detected in various chemoresistant cancers and represents a primary therapeutic target for reversing multidrug resistance 2, 3
Secondary Mechanisms Contributing to MDR
Decreased Drug Uptake
Low organic cation transporter-1 (OCT-1) activity reduces cellular uptake of certain chemotherapeutic agents like imatinib, with patients showing low OCT-1 activity experiencing highly dose-dependent responses 1
Inadequate plasma drug concentrations may result from excessive binding to plasma proteins (such as alpha-1-glycoprotein with imatinib), reducing therapeutic drug availability 1
Genetic Mutations
Point mutations in drug target genes (such as BCR-ABL kinase domain mutations in CML) alter protein conformation and prevent drug binding, with T315I mutation conferring the highest resistance to multiple tyrosine kinase inhibitors 1
Gene amplification of drug targets or resistance genes can increase expression levels of proteins that confer resistance 1
MicroRNA Dysregulation
Downregulation of specific microRNAs (miR-381, miR-495, miR-491-3p) that normally suppress MDR1 gene expression leads to increased P-gp production and enhanced drug efflux 5, 6
Upregulation of oncogenic microRNAs delivered via extracellular vesicles can silence tumor suppressor genes and apoptosis-related genes, promoting chemoresistance 1
Extracellular Vesicle-Mediated Resistance
Small extracellular vesicles (sEVs/exosomes) transfer resistance-conferring molecules between cancer cells, including non-coding RNAs and proteins that modify recipient cell phenotypes 1
Exosomal cargo includes microRNAs that act as competing endogenous RNAs (ceRNAs), sponging tumor-suppressive miRs and increasing oncogene expression, thereby promoting proliferation and inhibiting apoptosis 1
Tumor microenvironment components (carcinoma-associated fibroblasts, tumor-associated macrophages, mesenchymal stem cells) release sEVs that condition resistance to cytostatic drugs 1
Clinical Implications and Pitfalls
Key Considerations
P-gp substrate specificity varies, with dasatinib and nilotinib cellular uptake being independent of OCT-1 expression, unlike imatinib, making them potentially effective alternatives in resistant cases 1
Monitoring plasma drug levels remains controversial, with conflicting data on correlation with therapeutic response, and clinical value has not been definitively established 1
Resistance mechanisms often coexist, with multiple pathways contributing simultaneously to the MDR phenotype in individual patients 2, 3
Common Pitfalls to Avoid
First and second-generation P-gp inhibitors (verapamil, cyclosporine A, valspodar) have shown limited clinical success and may increase chemotherapy side effects by blocking physiological drug efflux from normal cells 3
Third-generation modulators (biricodar, zosuquidar, laniquidar) have produced disappointing results in clinical trials, suggesting that the "perfect reverser" may not exist 3
Attempts to increase response rates using additional cytotoxic agents or MDR modulators have generally failed 1