February 20, 2020
Matthew C. Fadus, Cecilia Lau, Jai Bikhchandani , Henry T. Lynch
Natural plant products have been used as the foundation of several medical treatments in humans. Although modern aspects of Western medicine have become the forefront of clinical practice today, natural plant products continue to be used as remedies in alternative medicine throughout the world.
It has been estimated that of the 877 small-molecule drugs introduced worldwide between 1981 and 2002, approximately 61% can be traced back to their origins in natural products.
Natural products are not only effective but are relatively non-toxic and have therapeutic doses well below their toxic levels. Curcumin is one such molecule that has shown promise since time immemorial.
Curcumin is the principle component of turmeric, a curry spice used as an edible component through different parts of Asia, mainly for its flavor and color profile and less so for its medicinal properties. In Ayurvedic medicine, curcumin is used as treatment for a variety of health conditions, including respiratory illness, liver disorders, inflammatory disorders and diabetic wounds.
In ancient Hindu medicine, it was used topically to treat sprains and swelling.In traditional Chinese medicine, curcumin is mainly used in treat mentfor conditions associated with abdominal pain.
Curcumin has been confirmed by scientific research to be anti carcinogenic, antimicrobial, hepatoprotective, cardioprotective and thrombo-suppressive.
The purpose of this article is to comprehensively review the literature on curcumin and its application in the field of medicine.
Curcumin is a highly pleiotropic molecule with numerous targets and mechanisms of action, including altering the activity of enzymes, growth factor receptors, cofactors, and other molecules. Curcumin acts to modulate several pathways.
The wide range of action of curcumin can be demonstrated by its activity in inhibiting lipoxygenase by binding lipoxygenase itself orbinding to phosphatidylcholine micelles. Curcumin also inhibitstumor invasion and angiogenesis by irreversibly binding CD13/ aminopeptidase. It has also shown both in-vitro and in-vivo to block aggregation and fibril formation by directly binding small β amyloidspecies.
Curcumin affects tumor growth by disrupting the activity of several enzymes that allow for growth and proliferation. Its antifibrotic effects in glomerular disease is suggested in its action of blocking fibrosis in anti-Thy1 glomerulonephritis through up regulation of hemoxygenase-1 gene expression. Hemoxygenase-1 gene expression can also be induced by curcumin through the generation of reactive oxygen species (ROS), p38 activation, and phosphatase inhibition.
Curcuminwas shown in a study to strongly inhibit FPTase activity, there by inhibiting the mevalonate pathway and blocking the transforming effects of Ras oncogenes expression. Curcumin has also been shown to inhibit xanthine oxidase activity, an enzymethat generates ROS, in PMA-treated NIH3T3 cells to inhibit PMAmediatedtumor promotion.
Mutations in tyrosine kinases cause uncontrolled activations that result in malignant transformation, growth, and metastasis ofhuman cancers. Curcumin's effect on the activity of multiple kinases furthers the suggestion of its role in cancer therapy. Research shows that curcumin inhibits EGFR kinase activity and EGFR-induced tyrosine phosphorylation of EGFR in A431 cellsand degrades cells of Her2/neu protein in-vitro.
Curcumin has also demonstrated that it has the ability to induce apoptosis inacute T-cell leukemia through inhibition of the phosphatidylinositol-3 kinase/AKT pathway and has also shown to induce G2/M arrest and non-apoptotic autophagic cell death inmalignant glioma cells by abrogating Akt and Erk signaling pathways.Additionally, Curcumin can inhibit many pathways that contribute to its anti-inflammatory and anti-carcinogenic effects,such as various MAPK pathways leading to activation of the p44/42MAPK (aka ERK1/ERK2), JNK, or p38 MAPK pathway.
Other mechanisms of cancer proliferation are involved in inhibitionof apoptosis, cell invasion, and adhesion for metastasis. Curcumin affects these pathways by being a potent inhibitor of TNF-a induced expression of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in a study using human umbilical vein endothelial cells. In human prostate cancer, curcumin can activate p53 and simultaneously down-regulate MDM2 oncogene expression via the PI3K/mTOR/ETS2 pathway in human prostate cancer(PC3) and colon cancer (HT-29) cell lines. It can also induceapoptosis and nuclear translocation and activation of p53 inhuman neuroblastoma cells.By inhibiting the activation of transcription factors, curcumincan affect the expression of genes that contribute to carcinogenesis,inflammation, cell survival, cell proliferation, invasion, and angiogenesis.
Prior studies have discussed the difficulty in achieving optimumtherapeutic concentrations of the molecule due to low solubility and poor bioavailability of curcumin. Studies suggest that curcumin is first biotransformed to dihydrocurcumin and tetrahydrocurcumin, and subsequently converted to monoglucuronide conjugates.
Preliminarily animal studies demonstrate that curcumin is rapidly metabolized and conjugated in the liver, and then excreted in feces with limited systemic bioavailability. Due to the low bioavailability of curcumin, The racurmin, a synthetically
derived nano-particle form of curcumin was developed that has a higher bioavailability
One of the most promising properties of Curcumin is its ability as an anti-inflammatory agent. One disease that is very common and is associated with an ongoing inflammatory process is rheumatoidarthritis. Curcumin can also be used to modulate the immune response after organ transplantation, as one trial demonstrated curcumin'sability to improve early graft function post-renal transplant.
Studies have demonstrated that curcumin has the ability to upregulatethe antioxidant hemoxygenase-1, which improves outcomes in kidney graft function. Another common medical condition that can be treated with curcumin is atherosclerosis, which is widely prevalent in the Western society. Although there are numerous explanations for this pattern of atherosclerotic disease, one of the factors that may play arole is the decreased consumption of natural plant-based products such as curcumin in the Western diet.
Curcumin has demonstrated some efficacy in treating hypercholesterolemia. Curcumin is also believed to play a role in preventing the pathogenesis of some psychiatric conditions as well. There has been some evidence that curcumin possesses the ability to bindbeta-amyloid plaques and reduce the plaque burden, thus slowing the progression of early Alzheimer's disease.
Curcumin has demonstrated therapeutic effects in patients suffering from inflammatory bowel disease (IBD). Inflammation ofthe digestive tract seen in Crohn's disease and ulcerative colitis can be a debilitating disease and long-standing inflammation mayalso increase the risk of colorectal cancer.
Today there are clinical trials using curcumin to treat pancreatic, hepatocellular, gastric, breast, prostate, skin, lung and colon cancer,as well as multiple myeloma. In an attempt to redefine colorectal cancer treatment, researchin the last few years has focused attention to the colorectal cancerstem cells (CSCs), which are suspected to account for cancer recurrence, relapse, and metastasis.
The stem-cell theory postulates that only a very small number of cells are responsible for driving malignancies. It is estimated that these CSCs may account for only 0.04% of all colorectal cancer cells.However, failure to eliminate the CSCs could explain recurrence, as the CSCs have self-renewing properties and drive the expansion of malignancy.
CSCs have similar properties to physiologic stem cells, and also maintain the tumor microenvironment, which in itself enhances carcinogenesis, metastasis, and invasion. In theory, therapies that target CSCs should limit tumor growth, relapse and metastasis.In one study it was found out that in-vitro curcuminadministration with 5-FU not only profoundly modulated communication between fibroblasts and CSCs, but also demonstrateda significant decrease in CSCs.
As for the adverse effects of curcumin, they appearto be minimal, and some are often isolated findings. Adverse effects of curcumin at high doses include gastrointestinal disturbances, inhibition of sperm motility in-vitro,inhibition of hepcidin synthesis, iron chelation, transient rises in liver enzymes, suppression of platelet aggregation, contact dermatitis andurticaria.
The historical use of curcumin as a therapeutic natural plant product dates back hundreds of years ago, but the most recent advances regarding this agent have extended the possibilities of its use as therapy. The novel idea of supplementing chemotherapy or treating common medical conditions with a traditional kitchen spice is an exciting yet challenging step in medicine. It is hoped that the results of the current laboratory and clinical trials not only help prove the effectiveness of curcumin, but also that they may serve as catalystsfor future research in large-scale clinical trials to demonstrate the efficacy and safety of curcumin for the treatment of a multitude of human diseases.
Matthew C. Fadus. et al. Curcumin: An age-old anti-inflammatory and anti-neoplastic agent. 2016