Overcoming P-Glycoprotein-Mediated Doxorubicin Resistance

Abstract

Intracellular concentration of doxorubicin in target cancer cells is a major determinant of therapeutic success of doxorubicin-based regimens. As known, doxorubicin is a substrate of P-glycoprotein (P-gp), the drug efflux transporter in the ABC superfamily. High expression level of P-gp in cancer cells can prevent intracellular accumulation of doxorubicin up to its effective level, leading to doxorubicin resistance and treatment failure. Moreover, these P-gp-overexpressed cells display multi-drug resistance (MDR) phenotype. Regarding this, application of P-gp modulators (suppressor of P-gp activity and expression) is likely to reverse MDR and restore cell sensitivity to doxorubicin treatment. In searching for potential chemo-sensitizer against resistant cancer, a number of phytochemicals or dietary compounds have been studied extensively for their P-gp modulating effects. Furthermore, combination between doxorubicin and P-gp modulators (e.g., plant-derived compounds, siRNA) given through specific target delivery platforms have been an effective strategic approach for MDR reversal and restore doxorubicin effectiveness for cancer treatment.

In Doxorubicin-Adapted Hodgkin Lymphoma Cells, Acquiring Multidrug Resistance and Improved Immunosuppressive Abilities, Doxorubicin Activity Was Enhanced by Chloroquine and GW4869

“…Several mechanisms are involved in the acquired resistance to doxorubicin [33]. One such mechanism is usually associated with the increased expression of the drug efflux transporters [34]. We found only a slightly increase in the mRNA levels of MRP1 in HRSdx cells and of MDR1 in KM-H2dx cells [9], outlining the poor role of these drug transporters in the acquired doxorubicin resistance in cHL tumor cells.…”

“…We more deeply investigated the possible mechanisms known to be involved in doxorubicin resistance [33] that include the following: increased expression of drug transporters [34]; different sub-cellular localization of doxorubicin [35]; increased response to oxidative stress [36]; decreased sensitivity to DNA damage [37]; autophagy [38]; extracellular vesicle (EV) release [39].…”

“…Over-expression of the efflux drug transporters MDR1/ABCB1 and MRP1/ABCC1 can cause doxorubicin resistance by increasing drug efflux [33,34]. In KMH-2dx cells, mRNA levels of MDR1 and of MRP1 were slightly up-regulated (Figure 5A).…”

Ultrasound Triggers Hypericin Activation Leading to Multifaceted Anticancer Activity

“…The cytofluorimetric analysis displayed a 2.4-fold increase in P-gp expression of HT-29/MDR cells compared with HT-29 cells ( Figure 8 b). Moreover, the cytotoxic effect of a chemotherapeutic drug that is a well-known P-gp substrate, doxorubicin [ 45 ], was evaluated at a concentration (100 μM) above its IC 50 value [ 46 ]. After 48 h of doxorubicin incubation, a significant decrease in HT-29 cell proliferation was observed, while no significant effect on cell proliferation was observed in HT-29/MDR ( Figure 8 c).…”