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| Curcumin is the main active ingredient in Turmeric. Member of the ginger family.Curcumin is a polyphenol extracted from turmeric with anti-inflammatory and antioxidant properties. - Has iron-chelating, iron-chelating properties. Ferritin. But still known to increase Iron in Cancer cells. - GSH depletion in cancer cells, exhaustion of the antioxidant defense system. But still raises GSH↑ in normal cells. - Higher concentrations (5-10 μM) of curcumin induce autophagy and ROS production - Inhibition of TrxR, shifting the enzyme from an antioxidant to a prooxidant - Strong inhibitor of Glo-I, , causes depletion of cellular ATP and GSH - Curcumin has been found to act as an activator of Nrf2, (maybe bad in cancer cells?), hence could be combined with Nrf2 knockdown -may suppress CSC: suppresses self-renewal and pathways (Wnt/Notch/Hedgehog). Curcumin — Curcumin is a turmeric-derived polyphenolic curcuminoid and diarylheptanoid from Curcuma longa, functionally best classified as a natural-product small molecule / nutraceutical candidate with pleiotropic redox, inflammatory, transcriptional, metabolic, and chemosensitizing activity. The standard abbreviation is CUR. It is the principal active pigment of turmeric rhizome, usually studied as purified curcumin, curcuminoid mixtures, turmeric extract, phytosomal curcumin, liposomal curcumin, nanoparticle curcumin, or piperine-enhanced formulations. Its oncology relevance is mechanistically broad but clinically constrained by poor aqueous solubility, rapid metabolism, low free systemic exposure, formulation variability, and insufficient well-powered cancer outcome trials. Primary mechanisms (ranked):
Bioavailability / PK relevance: Conventional oral curcumin has poor systemic bioavailability because of low solubility, low absorption, rapid conjugation, and rapid elimination. Oral trials have used doses up to gram-level daily dosing, but circulating free curcumin is typically low; measured plasma exposure often reflects conjugated curcumin. Piperine, phospholipid/phytosome, micellar, liposomal, nanoparticle, and other enhanced formulations can raise exposure, but each formulation should be treated as a distinct translational entity. Delivery constraints are central for oncology interpretation. In-vitro vs systemic exposure relevance: Common in-vitro anticancer concentrations, often in the low-to-mid micromolar range and sometimes higher, frequently exceed achievable free plasma exposure from standard oral curcumin. Therefore, direct systemic anticancer claims from cell culture should be weighted cautiously unless supported by tissue-local exposure, enhanced formulation data, local delivery, IV/liposomal delivery, or clinically measured pharmacodynamic biomarkers. Clinical evidence status: Preclinical evidence is extensive; human oncology evidence is mainly small human, biomarker, pilot, chemoprevention, adjunctive, symptom-management, and formulation trials. Current authoritative oncology summaries judge evidence inadequate to recommend curcumin-containing products as cancer treatment or as routine adjunct anticancer therapy, although symptom-support areas such as oral mucositis, radiation dermatitis, oxidative-status measures, and quality of life have more suggestive but still confirmatory-level evidence. Clinical studies testing curcumin in cancer patients have used a range of dosages, often between 500 mg and 8 g per day; however, many studies note that doses on the lower end may not achieve sufficient plasma concentrations for a therapeutic anticancer effect in humans. • Formulations designed to improve curcumin absorption (like curcumin combined with piperine, nanoparticle formulations, or liposomal curcumin) are often employed in clinical trials to enhance its bioavailability. -Note half-life 6 hrs. BioAv is poor, use piperine or other enhancers Pathways: - induce ROS production at high concentration. Lowers ROS at lower concentrations curcumin can act as a pro-oxidant when blue light is applied - ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓ - Lowers AntiOxidant defense in Cancer Cells: GSH↓ Catalase↓ HO1↓ GPx↓ but conversely is known as a NRF2↑ activator in cancer - Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑, - lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : TNF-α↓, IL-6↓, IL-8↓ - inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, uPA↓, VEGF↓, NF-κB↓, CXCR4↓, SDF1↓, TGF-β↓, α-SMA↓, ERK↓ - reactivate genes thereby inhibiting cancer cell growth : HDAC↓, DNMT1↓, DNMT3A↓, EZH2↓, P53↑, HSP↓, Sp proteins↓, - cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓, CDK6↓, - inhibits Migration/Invasion : TumCMig↓, TumCI↓, ERK↓, EMT↓, TOP1↓, TET1↓, - inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, HK2↓, ECAR↓, OXPHOS↓, GRP78↑, GlucoseCon↓ - inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, FGF↓, PDGF↓, EGFR↓, Integrins↓, - inhibits Cancer Stem Cells : CSC↓, CK2↓, Hh↓, GLi1↓, CD133↓, CD24↓, β-catenin↓, n-myc↓, sox2↓, OCT4↓, - Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK↓, ERK↓, JNK, TrxR**, - Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective, - Selectivity: Cancer Cells vs Normal Cells Curcumin Cancer Mechanism Ranking
TSF legend: P: 0–30 min R: 30 min–3 hr G: >3 hr |
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| A bioenhancer is an agent capable of enhancing bioavailability and efficacy of a drug with which it is co-administered Query Database for BioEnhancers but the bioenhancers mainly show up under the target notes Bioenhancers - piperine and quercetin are considered bio-enhancers - genistein Piperine act by suppressing P-gp and cytochrome P450 enzymes, which counteract the metabolism of rifampicin via these proteins, thus enhancing the oral bioavailability of rifampicin. It also decreases the intestinal production of glucuronic acid, thus allowing more substances to enter the body in active form. It was found to increase the bioavailability of various drugs from 30% to 200%.[25] Table 1: Published research on bioenhancer effect of piperine with various medicines Drug Studied in Reference Antimicrobial agents Rifampicin In vitro Balakrishnan et al, 2001[11] Isoniazid Rabbits Karan et al, 1998 [12] Pefl oxacin Mountain Gaddi goats Madhukar et al, 2008[13] Tetracycline Rats Atal et al, 1980[14] Sulfadiazine Rats and dogs Atal et al, 1980[14] Oxytetracycline Poultry birds Singh et al, 2005[15] Ampicillin Rabbits Janakiraman and Manavalan, 2008[16] Norfl oxacin Rabbits Janakiraman and Manavalan, 2008 [16] Nevirapine Adult males Kasibhatta et al, 2007 [17] Metronidazole In vitro Singh et al, 2010[18] Analgesics Diclofenac sodium Albino mice Pooja et al, 2007[19] Pentazocine Albino mice Pooja et al, 2007[19] Nimesulide Mice Gupta et al, 1998[20] Antiepileptics Carbamazepine In vitro Pattanaik et al, 2009 [21] Phenytoin Human volunteers Bano et al, 1987[22] Pentobarbitone Rats Majumdar et al, 1990[23] Other drugs Propranolol In vitro Bano et al, 1991 [24] Theophylline In vitro Bano et al, 1991 [24] Nutrients In vitro Pooja et al, 2007 [19 ***Borneol -Borneol is thought to temporarily open tight junctions between endothelial cells, enhancing drug penetration. It may also downregulate efflux transporters such as P-glycoprotein (P-gp), allowing higher intracellular concentrations of co-administered drugs. -presence of urea (as a carrier) increased the aqueous solubility of capsaicin by 3.6-fold compared to pure capsaicin Quercetin is found in citrus fruits and is a dual inhibitor of cytochrome P 3A4 (CYP3A4) and P-gp. Table 2: Effect of quercetin pretreatment/co-treatment on pharmacokinetic parameters of different drugs Drugs combined Increase in pharmacokinetic parametera Cmax AUC ABA Verapamil Two fold Two fold SH Diltiazem SH SH Not known Paclitaxel SH SH T wo fold Digoxin 413% 170% Not known Tamoxifen SH SH 59% Compared to drug in question alone. Cmax, peak plasma concentration; AUC, area under the curve; ABA, absolute bioavailability; SH, significantly higher. Another flavonoid, genistein belongs to the isoflavone class of flavonoids. It is a well-known phytoestrogen. The presence of genistein (10 mg/kg) caused an increase in AUC (54.7%) and a decrease in the total plasma clearance (35.2%) after oral administration of paclitaxel at a dose of 30 mg/kg in rats.[37] Naringin is the major flavonoid glycoside found in grapefruit and makes grapefruit juice taste bitter. Oral naringin (3.3 and 10 mg/kg) was pretreated 30 min before and after intravenous administration of paclitaxel (3 mg/kg), the AUC was significantly improved (40.8% and 49.1% for naringin doses of 3.3 and 10 mg/kg, respectively).[38 Carum carvi/Cuminum cyminum ( Jeera) Carum carvi seeds are a prized culinary herb. Extracts of its parts increased significantly (25%–300%), the bioavailability of a number of classes of drugs, such as antibiotics, antifungals, antivirals, anticancer, cardiovascular, anti-inflammatory/ antiarthritic, anti-TB, antileprosy, antihistaminic/respiratory disorders, corticosteroids, immunosuppressants, and antiulcers. Such extracts either in the presence or absence of piperine have been found to be highly selective in their bioavailability/bioefficacy-enhancing action.[40] Capmul One of the widely used bioenhancers is Capmul MCM C10, a glyceryl monocaprate, produced from edible fats and oils and is commonly used in lip products. In a study in rats, antibiotic ceftriaxone when given concomitantly with capmul, increased the bioavailability of ceftriaxone by 80%.[41] Nitrile glycoside Nitrite glycoside is a bioenhancer for drugs and nutrients. Novel bioactive nitrile glycosides, niaziridin and niazirin is obtained from the leaves, pods, and bark of Moringa oleifera. [42] An immunoenhancing polysaccharide and niaziminin, having structural requirement to inhibit tumor promoter-induced Epstein–Barr virus activation have been reported from the leaves of Moringa.[43,44] It enhances the bioactivity of commonly used antibiotics, such as rifampicin, tetracycline, and ampicillin, and also facilitate the absorption of drugs, vitamins, and nutrients through the gastrointestinal membrane, thus increasing their bioavailability. [41] Niazirin is another bioactive nitrile glycoside belonging to M. oleifera. [45,46] Process of isolation of nitrite glycoside from M. oleifera has been patented (US 6858588) by Khanuja et al in 2004–2005. [42 Mechanism of Action Of Bioenhancers Bioavailability-enhancing activity of natural compounds from the medicinal plants may be attributed to various mechanisms, such as P-gp inhibition activity by flavone, quercetin, and genistein; [51] inhibition of efflux transporters, such as P-gp and breast cancer resistance protein (BCRP),[52,53] by naringin and sinomenine thus preventing drug resistance; DNA receptor binding, modulation of cell signaling transduction, and inhibition of drug efflux pumps[54-56] ; by stimulating leucine amino peptidase and glycyl–glycine dipeptidase activity, thus modulating the cell membrane dynamics related to passive transport mechanism as seen with piperine [57] ; nonspecific mechanisms, such as increased blood supply to the gastrointestinal tract, decreased hydrochloric acid secretion, preventing breakdown of some drugs[6] ; and inhibition of metabolic enzymes participating in the biotransformation of drugs, thus preventing inactivation and elimination of drugs and thereby, increasing their bioavailability. [57-5] |
| 1792- | CUR, | LEC, | Chondroprotective effect of curcumin and lecithin complex in human chondrocytes stimulated by IL-1β via an anti-inflammatory mechanism |
| - | in-vitro, | Arthritis, | RAW264.7 | - | NA, | NA, | HCC-38 |
| 649- | EGCG, | CUR, | PI, | Targeting Cancer Hallmarks with Epigallocatechin Gallate (EGCG): Mechanistic Basis and Therapeutic Targets |
| - | Review, | Var, | NA |
| 873- | QC, | RES, | CUR, | PI, | Combination Effects of Quercetin, Resveratrol and Curcumin on In Vitro Intestinal Absorption |
| - | in-vitro, | Nor, | NA |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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