The Synergistic Role of Phenolic Compounds in Docetaxel Chemoresistance in Prostate Cancer: A Systematic Review and Meta-Analysis
Ramanjireddy Tatiparthi, Alaa A. A. Aljabali, Yachana Mishra, Vijay MishraBackground:
Docetaxel (DTX) is the first-line treatment for androgen-deprived prostate cancer. Its long-term therapeutic stress provokes therapeutic resistance via compensatory pathways. Several phenolic compounds have demonstrated synergistic effects on DTX chemosensitization; these quantitative measures have not yet been addressed. This study aims to identify the best adjunct phenolic compound that demonstrates synergy with DTX chemosensitization.
Methods:
A comprehensive search was conducted in accordance with the PRISMA 2020 guidelines. Independent authors searched six databases for in vitro or in vivo studies until September 2025. The outcomes measured included the mean combination index (CoI), the fold-change in IC50, apoptosis, proliferation, migration, and tumor volume inhibition. Their results were pooled in a random-effects model to estimate the standard mean difference relative to control studies. The risk of bias was assessed using SciRAP for in vitro studies and ARRIVE 2.0 for in vivo xenograft studies.
Results:
Twelve preclinical studies met the eligibility criteria. The phenolic compounds with synergistic effects in combination with DTX were Curcumin (CCM), Quercetin (QUR), Caffeic Acid Phenethyl Ester (CAPE), and Honokiol (HKI). The meta-analysis study revealed significant apoptosis induction (SMD = 1.83; 95% CI: 0.92–2.75), IC50 values (SMD=2.00; 95% CI:0.88, 4.52), and tumor growth reduction (SMD = –3.15; 95% CI: –4.62 –1.68). The mechanisms of resistance reversal pathways identified included NF-κB, PI3K/AKT, and STAT3 inhibition, as well as blocking, reversing, and downregulating the P-glycoprotein efflux pump to overcome DTX resistance.
Discussion:
Among the tested compounds, CCM and CAPE demonstrated the highest synergistic potency, as indicated by combination index values and fold-change in IC50. QUR showed superior anti-proliferative activity in DTX-resistant cell lines, and HKI achieved the most significant in vivo tumor regression (SMD = −7.56). RES showed predominantly additive activity and is included for comparative analysis. However, the combination index was the lowest for CCM, demonstrating the highest synergistic activity among the methods and models employed. Curcuminoids, such as calebin A, tetrahydrocurcumin, and hispolon, are recommended for further in vitro studies. The risk of bias assessment indicated high methodological reliability among the in vitro studies and moderate quality in the animal studies.
Conclusion:
Overall, phenolic compounds were found to be credible adjuncts to the DTX combination. Among them, CCM was found to be the most synergistic agent across all tested methods. However, further clinical studies are warranted in prostate cancer patients.