Encyclopedia
Curcumin is a pigment with a strong yellow colour found and the main active component of Curcuma longa, a perennial Zingiberaceae plant native to southwest India, but now grown across the South and Southeast Asia, especially in China and India. It is used for centuries as a spice and currently it is viewed as a nutraceutical due to the increasing number of scientific studies demonstrating its anti-oxidant, anti-inflammatory, anti-tumoral and cancer preventive properties. Its chemical structure comprises two aromatic ring systems with o-methoxy phenol groups connected by a seven-carbon linker consisting of an α,β-unsaturated β-diketone with tautomerism when in solution.
- cancer chemotherapy
- clinical trials
- Turmeric
- Cytokines
- inflammatory enzymes
- matrix metalloproteinases
1. History and Sources of Curcumin
The history of curcumin dates back about five thousand years. Curcumin is the main active ingredient of turmetic, a spice obtained by grinding the dried rhizomes of the plant Curcuma longa. [1,2,3]. Turmeric is referenced in Ayurvedic medicine, the characteristic medicinal system of Ancient India, as a home remedy for various diseases [4]. The expansion of the therapeutic use of curcumin to the Western civilizations dates from the time of the Portuguese "State of India", in the XVI century as it was mentioned by Garcia de Orta, the physician of the Viceroy of India, as “a medicine for jaundice” [5].Turmeric dry rhizome is composed mainly of starch, having also carbohydrates, proteins, lipids, fiber, curcuminoid pigments, sesquiterpenes (turmerone, atlantone, zingiberone, turmeronol, germacrone, α-curcumene, β-sesquiphellanderene, bisacurone, curcumenone, dehydrocurdione, procurcumadiol, bis-acumol, curcumenols, zedoaronediol, bisabolene, and curlone), and caffeic acid [6,7]. The curcuminoid content typically varies between 2% and 9%. Curcumin is the most abundant curcuminoid in turmeric, but traces of its precursors, desmethoxycurcumin and bisdemethoxycurcumin (Figure 1), are also present [8].
Besides turmetic, curcumin and its analogues can be found in Curcuma mangga, Curcuma zedoaria, Costus speciosus, Curcuma xanthorrhiza, Curcuma aromatica, Curcuma phaeocaulis, Etlingera elatior, and Zingiber cassumunar [9]. C. mangga is commonly named mango ginger and considered as a good dietary source of curcumin, although it is still far from reaching the widespread reputation of turmeric as a dietary supplement and functional food.
Figure 1. The three main curcuminoids found in Curcuma longa.
In western societies, turmeric consumption is a growing trend due to the recognition of its therapeutic properties against inflammation and cancer [10,11]. Turmeric has been granted the GRAS status (‘Generally Recognized as Safe’) by the FDA [12], with an allowed daily intake (ADI) limit of 2.5 mg/kg of body weight; for pure curcumin, the ADI is of 0.1 mg/kg weight [13]. The official acknowledgement of turmeric as a safe dietary supplement contributed strongly to its widespread use and expansion to other areas such as cosmetics. Since 2013, turmeric is the top-ranking herbal supplement in North America, with sales of that year having grown 26.2% [14]. India is the largest producer of curcumin and North America its largest market, with revenues over US$20 million in 2014 [15] and expected to grow up to a global value of $94.3 billion in 2022 [16].
2. Curcumin Chemistry
The isolation of the active phytochemicals in turmeric dates back to 1815, when the first crude extract was obtained and described as “a matter of yellow color” [17]. Many of the properties of curcumin could already be observed in this extract: it was insoluble in water, solubilizing upon the addition of alkali to form a reddish-brown solution, and able to react with salts of metals such as lead and tin [17]. The extract was later found to contain a mixture of curcuminoids along with some oils and resins. Curcumin was purified in 1870, having been isolated as orthorhombic crystals [18]. Its chemical structure was determined in 1910 [19].
Curcumin has the chemical formula C21H20O6 (Mw of 368.38): it is also referred to as diferuloylmethane, having a very long IUPAC denomination: (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione. Its chemical structure comprises two aromatic ring systems with o-methoxy phenol groups connected by a seven-carbon linker consisting of an α,β-unsaturated β-diketone moiety that exhibits keto-enol tautomerism in solution [20]. Due to extended conjugation, the π electron cloud is distributed all along the molecule making curcumin very hydrophobic, with a log p value of 3.38 and an extremely low solubility in water (1.34 ± 0.02 mg/L) [21]. According to the Biopharmaceutics Classification System (BCS) [22], curcumin is a class IV drug; that is, a compound having low solubility and low permeability. Class IV drugs usually are “not well absorbed over the intestinal mucosa and a high variability [in the absorption profile] is expected”.
Curcumin is reasonably stable in water at pH < 7.0 due to structural stabilization by the conjugated diene; in PBS and at pH > 8 it may degrade rapidly (10 min) [2]. In fact, curcumin possesses three ionizable protons with pKa values of approximately 8.5 (enolic proton) and 10–10.5 (two phenolic protons) [23,24].
Curcumin absorbs light from the near ultraviolet (around 340 nm) to the indigo-blue spectral region (450–460 nm), with absorption peaking at 410–430 nm (violet light) [25]. It presents a fluorescence band between 460 and 560 nm. Furthermore, curcumin is sensitive to ultraviolet radiation and its degradation is accelerated by exposure to sunlight [26,27]. When irradiated with light above 400 nm, curcumin undergoes a self-sensitized photo-decomposition where singlet oxygen is involved, but when reactive oxygen species are not available, other decomposition mechanisms are triggered. Photodegradation products include vanillin, vanillic acid, 4-vinyl-guaiacol, ferulic aldehyde, and ferulic acid [28].
3. Biological Actions of Curcumin
Curcumin is indicated in ayurvedic medicine for an enormous variety of pathologies and ailments [29]. Most of this knowledge is, however, empirical, or it has not been demonstrated by studies on human subjects. Most of studies available in the literature have been conducted either in vitro or in animal models (mostly rodents). They provide information on possible therapeutic indications of curcumin for conditions as varied as viral infections, scleroderma, atherosclerosis, myocardial infarction, brain ischemia, and Alzheimer’s [30], but such activities may not necessarily be manifested in human patients. Only in the latest decades has evidence from clinical trials been gathered on curcumin. This section presents the most relevant results of clinical trials, with highlight on cancer therapy.
3.1. Medicinal Activity in Humans
Turmeric has well-documented anti-inflammatory [31,32], antioxidant [33,34,35,36] and antitumor activities [37,38,39,40] that are mainly attributed to curcumin. Curcumin is a strongly pleiotropic molecule, able to modulate the activity of numerous signalling biomolecules, to interfere with different cellular and molecular cascades [41,42] and to interact with transcription factors, growth factors or their receptors, nuclear factors, cytokines, and hormone receptors. Curcumin is even able to regulate the expression of genes associated with the processes of cell proliferation and apoptosis [43]. Details on the different biochemical targets of curcumin are given in the Section 3.2.
3.1.1. Curcumin against Inflammation and Oxidative Stress
Curcumin interferes with various steps of the arachidonic acid inflammatory cascade, inhibiting the enzymes phospholipase, cyclooxygenase II, and lipo-oxygenase, and having also effects on cytokines [44,45]. Curcumin was shown to reduce post-operative inflammation in patients having had surgical repair of inguinal hernia and/or hydrocele [46], to ameliorate symptoms of chronic inflammation pathologies such as arthritis [47,48], psoriasis [49], and bowel conditions (IBS, Crown’s disease, and ulcerative colitis) [31,50,51,52,53] and to treat eye inflammations such as the “idiopathic orbital inflammatory syndrome” [54] and uveitis [55].
The antioxidant activity of curcumin is also the result of a multiplicity of actions. Not only does curcumin stabilize superoxide and hydroxyl free radicals due to the electron-donating properties of its phenolic groups [20,56,57,58], but it also induces the expression of antioxidant enzymes. In vitro tests with beta cells of human pancreas islets incubated with curcuminoids have shown increased levels of heme oxygenase 1, gamma-glutamyl-cysteine ligase, and NAD(P)H:quinone oxidoreductase and a consequent increase in glutathione levels [59]. Curcumin protects against oxidative stress caused by advanced glycation end products in patients with diabetes, being under evaluation as a new anti-diabetes drug candidate in a series of clinical and pre-clinical studies [60]. It should also be highlighted that the antioxidant benefits of curcumin do not cease with its metabolization, as many of the metabolites present significant antioxidant properties [61].
3.1.2. Antitumoral Action
The first report on the anticancer activity of curcumin, in 1987 [62], rekindled the interest in this compound and brought it to the spotlight of the western society. Curcumin has been the subject of over 30 clinical trials in the context of cancer, some of them still ongoing.
-
In colorectal cancer, curcumin was studied for both tumor prevention and chemotherapy. In cancer prevention, it was demonstrated to reduce by 40% the formation of aberrant crypt foci in smoking patients (intake of 4 g/day for one month) [63]. In a combination study, curcumin, and quercetin (1440 + 60 mg/day for six months) were shown to reduce the number and size of polyps in patients with familial adenomatous polyposis, a hereditary disorder characterized by the development of hundreds of colorectal adenomas which turn malign when left untreated [64]. In chemotherapy, 1 g/day curcumin for up to one month (prior to surgical removal of the tumor) was shown to improve the patient’s body weight and to increase the apoptosis rates of the patient’s tumor cells [65].
-
In prostate cancer, a trial has demonstrated that curcumin/flavone association reduces the chances of developing cancer by lowering the levels of prostate-specific antigen (PSA). PSA levels are increased due to the presence of chronic inflammation in the prostate, which is one of the most significant causes of tumorigenesis [66]. Association of curcumin (5.4 g/day for seven days around chemotherapy) with docetaxel/prednisone (75 mg/m2 + 24 mg, once every three weeks, for six cycles) demonstrated encouraging results, with a tumor objective response in 40% and a PSA response in 59% of the patients in a group having castration-resistant prostate cancer [67]. There is also preliminary evidence on the ability to reduce the formation of metastases. An association of polyphenols (pomegranate seed, green tea, broccoli, and turmeric), taken over six months, has lowered PSA by 63.8% (compared to placebo) in prostatectomized patients [68]. Note that, since these men have no prostate, PSA is produced only by neoplastic cells, thus being a good indicator of metastasis growth. Curcumin can confer radioprotective effect in patients with prostate cancer who undergo radiation therapy, reducing the severity of radiotherapy related urinary symptoms. Patients were given 3 g of curcuminoids per day (corresponding to ca. 2 g/day of curcumin) for one week before the onset of radiotherapy and until completion of radiotherapy [69,70].
-
In breast cancer, curcumin was used in co-therapy with both chemotherapeutic agents and radiation. A combination therapy with docetaxel and curcumin (in escalating doses of up to 6 g/day) was found to afford better therapeutic results than docetaxel used alone: histological improvements were observed in the fourteen patients under study, all having reduction or elimination of disseminated foci [71]. Curcumin was evaluated in two clinical trials regarding protective action against radiation-induced dermatitis during radiotherapy of breast cancer patients. Despite promising results on a pilot study, with slightly less severe dermatitis in the curcumin group, a second trial on 686 patients showed no significant changes in pain, symptoms, and quality of life of the patients taking curcumin (1.5 g daily) in regard to those taking placebo [72].
-
Pancreatic cancer: a phase II study with twenty-one patients taking curcumin (8 g/day for up to 18 months) showed partial regression during the treatment period; patients had different responses after treatment, one of them having become stable and another one having shown a strong tumor relapse [73]. Another trial evaluated the association of curcuminoids (8 g/day, corresponding to 6.14 g/day of curcumin) with a gemcitabine-based chemotherapeutic treatment. A total of 21 patients was divided into two groups: one, with 2 patients, received gemcitabine monotherapy; the other, with 19 patients, received a combination therapy of gemcitabine and S-1. S-1 is a novel oral antitumor formula based on fluorouracil, comprising three pharmacological agents: (i) tegafur, a prodrug of 5-fluorouracil, (ii) 5-chloro-2,4-dihydroxypyridine, which inhibits dihydropyrimidine dehydrogenase activity; and (iii) potassium oxonate, which reduces gastrointestinal toxicity was also evaluated. Eighty-one percent of the patients died during the study period. In the surviving patients, the treatment was able to stabilize the disease [74].
3.2. Molecular Targets of Curcumin
The various targets and effects of curcumin are summarized in the Table 1 and described with more detail in the following sub-sections.
3.2.1. Curcumin Modulates the Activity of Transcription Factors
Three main families of transcription factors are involved in cell proliferation, cell invasion, metastasis, angiogenesis, and resistance to chemotherapy and radiotherapy. They are:
-
the families of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and of the activated protein-1 (AP-1),
-
signal transducers and activators of transcription (STAT), and
-
steroid receptors [77].
NF-kB is involved in cell response to several external agents, including physical strain, oxidative stress (free radicals), and cytokines. NF-kB is usually inactive in the cytoplasm, but once activated by the adequate stimuli it can translocate to the nucleus, inducing expression of apoptosis-suppressing genes to promote cell proliferation and even metastasis. Curcumin was shown to inhibit the activation of the NF-kB pathway by studies in vitro [78] and in vivo [79] and in a phase II clinical trial [80].
AP-1 is involved in the differentiation, proliferation, apoptosis, and oncogenic transformations of the cells [81]. AP-1 can be activated by stimuli of growth factors, cytokines, or bacterial/viral infections. Activated AP-1 induces the expression of several genes that code proteins involved in the angiogenesis and growth of cancer cells, such as cyclin-D1, MMP, and VEGF [82]. Curcumin inhibits this pathway by direct interaction with the AP-1 DNA-binding site, namely in human leukemia cells, transformed keratinocytes and prostate cancer cells [83,84,85,86,87]. The effect of curcumin on the expression of NF-kB and AP-1 members was evaluated in an oral cancer cell line [88]. Nuclear extracts obtained from curcumin-treated cancer cell were evaluated regarding binding of the transcription factors AP-1 and NF-kB, to reveal that binding is reduced in a dose dependent manner and that in cells treated with 100 μM of curcumin, the DNA-binding activities of AP-1 and NF-kB were completely lost. These results confirmed the downregulation of several transcription factors and inhibition of NF-kB and AP-1.
The Janus kinase (JAK) signal transducer of activators of transcription (STAT) pathway signalling pathway is a signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules, allowing these extracellular factors control gene expression and regulate cell growth and differentiation [89]. In cancer cells, this pathway is consistently active, being involved in metastasis. Inhibition of the JAK/STAT pathway by curcumin was observed in prostate, lung, and glioblastoma cancer cell lines [90,91,92]. Curcumin was shown to inhibit STAT3 phosphorylation and to lower levels of interleukin-6 (IL-6), a pro-inflammatory cytokine involved in cell proliferation and survival. Curcumin also exhibited antineoplastic effects in K652 chronic leukemia, ovarian, and endometrial cancer cells by suppression of JAK/STAT signalling [93,94].
Table 1. Molecular targets and cell processes modulated by curcumin.
| Family | Molecular Target | Effect | Ref |
|---|---|---|---|
| Transcription factors | NF-kB | ↓ | [78,79,80,88,95] |
| Nrf2 | ↑ | [96] | |
| AP-1 | ↓ | [83,84,85,86,87,88] | |
| STAT-3 | ↓ | [97,98] | |
| STAT-5 | ↓ | [99,100] | |
| β-catenin | ↓ | [101,102] | |
| EGR-1 | ↓ | [103,104] | |
| HIF-1 | ↓ | [105] | |
| Notch-1 | ↓ | [106] | |
| Growth factors | EGF | ↓ | [107] |
| FGF | ↓ | [108] | |
| PDGF | ↓ | [109] | |
| TGF-β | ↓ | [110,111,112,113,114] | |
| VEGF | ↓ | [115,116,117] | |
| Cytokines, pro-inflammatory | TNF-α | ↓ | [95,118,119,120] |
| IL-1 | ↓ | [121] | |
| IL-2 | ↓ | [122] | |
| IL-5 | ↓ | [123] | |
| IL-6 | ↓ | [118] | |
| IL-8 | ↓ | [121] | |
| IL-12 | ↓ | [124] | |
| IL-18 | ↓ | [125] | |
| Enzymes | COX-2 | ↓ | [72,80,126,127] |
| iNOS | ↓ | [127] | |
| Lipoxygenase | ↓ | [128] | |
| MMP-9 | ↓ | [78,129,130,131] | |
| Kinases | JNK | ↑ | [132] |
| MAPK | ↓ | [133] | |
| PKC | ↓ | [131] | |
| Akt | ↓ | [134] | |
| CDKs | ↓ | [135] | |
| Receptors | AR | ↓ | [86] |
| EGFR | ↓ | [79,119] | |
| Adhesion molecules | ICAM-1 | ↓ | [95] |
| VCAM-1 | ↓ | [95] | |
| ELAM-1 | ↓ | [95] | |
| Antiapoptotic proteins | Bcl-2 | ↓ | [136,137,138,139,140] |
| Bcl-xL | ↓ | [136,137,138,141] | |
| Proapoptotic proteins | Bax | ↑ | [136,137,138,139,140] |
| Bak | ↑ | [140] | |
| Others | Cyclin D1 | ↓ | [142,143] |
| p53 | ↑ | [144,145] |
3.2.2. Curcumin Decreases Tumor Angiogenesis
Curcumin has anti-angiogenic properties by inhibition of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) [79]. Several in vitro and in vivo studies have demonstrated the association between the suppression of VEGF expression by curcumin with its inhibitory action on tumor growth [115,116,117]. In vivo studies in mice showed that VEGF expression and angiogenesis suppression is mediated through suppression of the osteopontin gene expression and the NF-κB/ATF-4 pathway [115].
3.2.3. Curcumin Inhibits Inflammatory Cytokines
Tumor necrosis factor (TNF) and interleukins (IL) are two kinds of inflammatory cytokines with an important mediating role in tumorigenesis. Curcumin was shown to have profound effects on TNF inhibition in dendritic cells, macrophages, monocytes, alveolar macrophages, and endothelial and bone marrow cells [118]. The suppression of the TNF-signalling pathway by curcumin is related to the inhibition of NF-kB phosphorylation, as detailed in 2.2.1 [119,120].
Interleukins (ILs) contribute to tumor invasiveness and angiogenesis by induction of the expression of metalloproteinases, adhesion molecules and STATs [146]. Curcumin inhibits the expression of IL-1 [121], IL-2 [122], IL-5 [123], IL-6 [118], IL-8 [122], IL-12 [124], and IL-18 [125], being thus a potent inhibitor of these classes of cytokines.
3.2.4. Curcumin Regulates the Activity of Enzymes with Roles in Inflammation and Cancer
Pro-inflammatory enzymes are linked with various types of cancer. COX-2 is known to participate in uncontrolled cell proliferation and suppression of apoptosis, while inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-9 (MMP-9) are involved in the formation of metastases [147,148]. Several studies, both in vitro and in vivo, demonstrated that the inhibitory action of curcumin on COX-2 expression contributes significantly to its antitumor action [72,80,126]. Curcumin was also shown to inhibit the expression of MMP-9 in orthotopically implanted pancreatic [129] and ovarian [130] tumors in mice and the production of iNOS in chronic colitis [127].
3.2.5. Curcumin and Cell Cycle Regulation
Programmed cell death, or apoptosis, is a mechanism of vital importance in maintaining normal cell growth. Apoptosis is initiated by regulation of protein 53 (p53) and by proteins of the B-cell lymphoma 2 family (Bcl-2). Activated p53 induces activation of two pro-apoptotic proteins, Bcl-2 homologous antagonist killer (Bak), and Bcl-2 associated x protein (Bax), which in turn release cytochrome c into the cytoplasm to activate the caspase cascade. Curcumin is able to induce apoptosis in prostate cancer PC-3, DU-145, and LNCaP cells via p53-dependent mitochondrial pathways [145]. Activation of p53 by curcumin leads to over-expression of Bak, Bax, and several caspase proteins [136,137,138,139,140]. In addition, curcumin inhibits the activity of a few anti-apoptotic proteins, such as Bcl-2 and B-cell lymphoma extra-large protein (Bcl-XL) [136,137,138,139,140,141].
Cyclin-dependent kinases (CDKs) are also involved in the life cycle of cells, being in charge of its progression through the different stages [149]. Malignant cells have thus frequent alterations in CDK expression, with overexpression of cyclins and suppression of CDK inhibitors. Curcumin induces cell cycle arrest in colon cancer cells (HTC116 line) by CDK2-dependent effects [135]. The mechanism underlying cell cycle arrest by curcumin may involve overexpression of CDK inhibitors and blockage of the expression of cyclin E and cyclin D1 [142,143].
This entry is adapted from the peer-reviewed paper 10.3390/app10248990
