Reversing Multidrug Resistance in Cancer Using Phytochemicals: Targeting Efflux Pumps and Survival Pathways

Abstract

Multidrug resistance (MDR) is the principal cause of chemotherapy failure and is implicated in over 90% of deaths from advanced cancer. Its best-characterised driver is the overexpression of ATP-binding-cassette (ABC) efflux transporters—P-glycoprotein (P-gp/ABCB1), multidrug-resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2)—which actively extrude structurally diverse anticancer drugs and thereby lower their intracellular concentration. This transporter-mediated efflux acts in concert with dysregulated pro-survival and anti-apoptotic signalling (PI3K/AKT/mTOR, NF-κB, MAPK and Wnt/β-catenin), which both up-regulates the transporters and enables evasion of drug-induced apoptosis. Three generations of synthetic efflux-pump inhibitors have largely failed in the clinic because of intrinsic toxicity, poor selectivity and unfavourable pharmacokinetics. Phytochemicals—curcumin, resveratrol, quercetin, EGCG, tetrandrine, taxifolin, capsaicin, piperine and related natural products—have consequently emerged as a promising “fourth generation” of MDR reversers.
This review synthesises their dual mechanism of action: direct functional inhibition and transcriptional down-regulation of ABC transporters on the one hand, and suppression of the survival pathways that sustain the resistant, apoptosis-evading phenotype on the other. Compiled data show reversal folds of roughly 3–15 relative to chemotherapy alone, two- to threefold increases in intracellular drug accumulation, and strong synergy in combination indices. Because most phytochemicals suffer from low aqueous solubility and poor systemic bioavailability, nanocarrier co-delivery systems—which additionally provide tumour targeting and reduce exposure of healthy P-gp-expressing tissues—are examined as the key translational enabler. The review concludes that phytochemicals, deployed within rationally engineered co-delivery platforms and combination regimens, represent a credible and comparatively non-toxic strategy for reversing cancer MDR, while highlighting the standardisation, pharmacokinetic and clinical-validation gaps that remain