**4. Strategic approaches to overcome P-gp mediated resistance to doxorubicin**

Taken that doxorubicin is a known substrate of P-gp, the drug efflux transporters in the ATP binding cassette (ABC) family. Hence, any approaches target at the function of these transporters can be presumed to increase therapeutic success for doxorubicin-based chemotherapeutic regimens. Regarding this, the strategies are as follows:


The current MDR reversal strategy has been exploited P-gp modulators that either directly inhibit P-gp activity or down-regulate P-gp expression in order to restore cell chemo-sensitivity to doxorubicin [107]. With the encapsulation technology, P-gp modulators can be co-administered with doxorubicin in the same drug delivery platform, and enhance intracellular doxorubicin accumulation. This approach can be accomplished if the potent, non-cytotoxic P-gp modulators that specifically target at cancer cells are implemented. In addition, the P-gp modulators that also target at non-transporter based resistance such as activation of cellular

**199**

*Overcoming P-Glycoprotein-Mediated Doxorubicin Resistance*

increase accumulation of cytotoxic drugs in these tissues.

model, compared with doxorubicin alone [121–125].

**4.2 Drug delivery system and formulation**

survival pathways can exert potentially synergistic impact on MDR reversal effect and better response to doxorubicin treatment. Collectively, the combined doxorubicin and P-gp modulators with multiple-hit targets is a promising strategy to achieve chemotherapeutic efficacy without the need of high dose or additional cytotoxic

This approach aims to suppress P-gp activity at plasma membrane of target cancer

The fourth generation of P-gp modulators which are mostly natural products have gained a great interest as potential chemosensitizers in MDR cancer treatment. The advantages of being natural products with long history of use are inclined to the known safety profiles in human and potential hit multiple targets that can restore cell sensitivity to doxorubicin. In addition to direct inhibition of P-gp activity, a number of the natural compounds at non-cytotoxic concentration elicit their chemo sensitizing effects through down-regulation of MDR1 and signaling proteins in cell adaptive survival mechanisms. The higher degree of synergism between doxorubicin and a P-gp modulator can be anticipated with potential therapeutic success. Synergistic outcomes between doxorubicin and natural compounds such as resveratrol, quercetin, silymarin, gallic acid, curcumin, epigallocatechin-3-gallate have been demonstrated in various cancer cell models [82, 83, 103, 111, 117–120]. In addition to P-gp modulatory activity (inhibiting both P-gp function and expression), these natural compounds have a broad spectrum of pharmacological activities such as antioxidant, anticancer, anti-inflammation, possible through multiple signaling pathways. For example, the biological effects of curcumin have been related to multiple signaling pathways including NF-kB, Akt, MAPK, Nrf2, AMPK, JAK/STAT that involve in MDR1 expression, cell inflammation, and apoptosis [121]. Co-administration of doxorubicin and curcumin significantly improved doxorubicin-mediated cytotoxicity in vitro cell models and in vivo hepatic xenograft mice

In addition to chemical-based modulators, the uses of specific antibody against

This approach aims to develop targeted delivery platforms for improving the permeation of doxorubicin/P-gp modulators/ chemo-sensitizers (e.g., antibodies against ABCB1, siRNA) into target cancer cells, leading to an increased intracellular doxorubicin concentration [3, 89, 96, 126–128]. Various nano-drug delivery platforms such as polymeric and solid lipid nanoparticle (SLNs), liposomes, micelles, mesoporous silica nanoparticles, nanostructured lipid carriers, dendrimers have been constructed to better targeting drug delivery to site of action. This approach

P-gp or RNA interference (RNAi) technology to silence P-gp expression may be effective approach to suppress P-gp activity and restore chemo-sensitivity to doxorubicin treatment. Clinical studies on these MDR reversing methods should be

extensively conducted to support their uses and benefits in cancer patients.

cells. Several P-gp modulators in combination with anti-cancer drugs have been evaluated for safety and efficacy in clinical trials. The clinical outcomes from the first three generations of ABC inhibitors such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 were quite disappointed, partly because of their dose-limiting adverse events. Most of the P-gp inhibitors required high doses for their clinical MDR reversal effects. In addition, their interference on the P-gp or other ABC transporters at non-target tissues such as brain and kidney could adversely

*DOI: http://dx.doi.org/10.5772/intechopen.95553*

drugs in the therapeutic regimen.

**4.1 Synergy with P-gp modulators**

survival pathways can exert potentially synergistic impact on MDR reversal effect and better response to doxorubicin treatment. Collectively, the combined doxorubicin and P-gp modulators with multiple-hit targets is a promising strategy to achieve chemotherapeutic efficacy without the need of high dose or additional cytotoxic drugs in the therapeutic regimen.
