Curcumin

Curcumin erases cancer-promoting epigenetic marks by (i) targeting DNA methyltransferases (DNMT1/3B) to demethylate and re-express tumor-suppressor genes such as RARβ2, WIF-1 and Nrf2; (ii) inhibiting histone deacetylases (HDAC1/3/8) while selectively down-regulating the acetyltransferase p300/CBP to restore H3/H4 acetylation, activate p53 and silence NF-κB-driven inflammation; and (iii) remodeling the miRNA landscape—up-regulating miR-15a, miR-16, miR-22, miR-200 and let-7 families and down-regulating oncomiRs such as miR-21, miR-27a and miR-130a—to block proliferation, epithelial-to-mesenchymal transition and chemo-resistance. Such chromatin and non-coding-RNA changes work together to stop the cell cycle, promote apoptosis, restrain angiogenesis and reduce oxidative and inflammatory stress.
Curcumin also directly binds DNA grooves, regulates transcription factors (NF-κB, STAT3, AP-1, β-catenin) and inhibits proteasome kinase DYRK2 to stabilize p53 and further sensitize cancer cells. Complementary to classical cytotoxics, curcumin also reverses diabetes, neuro-degeneration and wound healing through similar antioxidant epigenetic actions.

Fig. 1 Pathways modulated by curcumin in tumor suppression and apoptosis. (Hassan F.; et al. 2019)

Normal oral bioavailability results in <1 µM plasma concentrations in humans, orders of magnitude below the 10-20 µM concentrations used in in-vitro studies. Nano-carriers, adjuvants and co-formulations augment tissue levels by up to 185-fold. Micelles, liposomes, solid-lipid particles, PLGA or gold nanoparticles, exosomes and cyclodextrin complexes can stabilize the keto-form against rapid glucuronidation, improve aqueous solubility, stabilize pH-sensitive enol tautomers, enable lymphatic uptake and facilitate blood-brain barrier translocation. In turn, this gives rise to observable effects in the intestine, liver, adipose tissue, heart, brain and tumors, including antioxidant, anti-inflammatory, antimicrobial and epigenetic effects.
Nano-curcumin reduces NAFLD, obesity, metabolic syndrome, atherosclerosis, myocardial infarction, IBD and neuro-degeneration, by down-regulating NF-κB, TNF-α, IL-6, iNOS, COX-2, GSK-3β and BACE1 and up-regulating Nrf2, AMPK, PPAR-γ and M2 macrophage polarization. Gut microbiota composition is also altered, with increased SCFA-producing taxa and microbial biotransformation to tetrahydrocurcumin.

Fig. 2 Curcumin nano-delivery systems. (Bertoncini-Silva C.; et al. 2024)