Curcumin

Executive summary: 

Curcumin is the polyphenol component derived from the extraction of rhizomes of Curcuma longa. There are several therapeutic advantages of using Curcumin in various chronic diseases such as inflammation, arthritis, metabolic syndrome, liver disease, obesity, neurodegenerative diseases and, above all, in several cancers. Although Curcumin is effective and safe in all aspects, it is still not approved as a therapeutic agent. The relative bioavailability of Curcumin is known as a significant issue for the same. Curcumin has shown mechanisms in the signaling pathways and molecular targets involved in developing different types of cancer. It is a natural anticancer agent and has been paid more consideration because of its inhibitory effect on the tumor. Curcumin target multiple pathways, which makes it an extremely potent anticancer agent. Very little clinical evidence suggests the exact and accurate effects of Curcumin on cancer. But, the clinical evidence shows that Curcumin is used to inhibit and control cancer, improving the clinical symptoms and preventing metastasis by combining it with other drug formulations.

Introduction to Curcumin

Curcumin is the polyphenol component derived from the extraction of Curcuma longa rhizomes (turmeric) ^​1​. It primarily belongs to the class of polyphenols, known as diferuloylmethane, constituting a molecular weight of 368.38 g and the chemical formula of C21H20O6. The Curcuma longa has been used in Asian countries as a medical herb due to its antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and anticancer properties for traditional purposes ^​2–6​. Its chemistry depends upon the various types of biological activities. Curcumin contributes to making up 2-8% of the turmeric compounds and is known to be the primary cause of the yellow color of turmeric and is recognized for the different characteristics of turmeric ^​7​. It tends to show lower inherent toxicity and efficacy in pharmacological development ^​8​. 

There are several therapeutic advantages of using Curcumin in various chronic diseases such as inflammation, arthritis, metabolic syndrome, liver disease, obesity, neurodegenerative diseases and, above all, in several cancers. It shows anti-proliferation, anti-inflammation, anti-angiogenesis and anti-oxidation ^​9–14​. It is known to produce phytochemicals for anticancer effects to be used in combination with any drug or alone. Its polyphenolic characteristics target multiple signaling molecules while representing the cellular activity that has shown efficacy in health benefits ^​15​. Its other health benefits include the advantages in inflammatory conditions, metabolic syndrome, pain and help in the management of inflammatory and degenerative eye conditions ^{​16–20​}.

Although Curcumin has shown tremendous therapeutic advantages, most of its benefits include antioxidant and anti-inflammatory effects. But its anti-inflammatory and antioxidant mechanisms have evolved one of the most common issues of ingesting Curcumin due to its poor bioavailability, poor absorption, rapid metabolism, and rapid elimination ^​21​. Hence, different agents are tested to improve the bioavailability of Curcumin, for which most of them aim to block the metabolic pathway of Curcumin.  

Curcumin is identified and utilized for various health benefits in different forms across the globe. In India, Curcumin is used as turmeric, in Japan as tea, in Thailand as cosmetics, as a colorant in China, as to drinks in Korea, antiseptic in Malaysia, anti-inflammatory agent in Pakistan. It shows other benefits in other regions of the world. Curcumin is available in capsules, tablets, ointments, energy drinks, soaps, and cosmetics. The FDA approved curcuminoids as “Generally Recognized As Safe” (GRAS), showing good tolerability and safe through several clinical trials when administered with different dosages 4000 and 8000 mg/day up to 12,000 mg/day for 95% concentration of three curcuminoids: Curcumin, bisdemethoxycurcumin, and demethoxycurcumin ^​22​. 

Bioavailability of Curcumin

Curcumin is an anti-inflammatory agent and has shown antioxidant, antimicrobial, and anticarcinogenic properties. Also, other health benefits include hepato- and neuroprotective agents, thrombosis suppressing, myocardial infarction protection, hypoglycemic, and antirheumatic effects. Several animal models and clinical studies on humans have ensured the safety of Curcumin even at high doses. Although Curcumin is effective and safe in all aspects, it is still not approved as a therapeutic agent. The relative bioavailability of Curcumin is known as a significant issue for the same. The less bioavailability of Curcumin within the body involves decreased intrinsic activity, increased metabolism, poor absorption, inactivity of metabolic products and faster elimination from the body. Some possible methods are integrated to overcome these problems- 

• Adjuvants constituting Curcumin are capable of blocking its metabolic pathways, which are the primary methods towards improving its bioavailability.
• The constituents of nanoparticles, liposomes, micelles, and phospholipid complexes are other promising ways to improve curcumin bioavailability.

The studies concerning the in Vitro and in vivo efficacy of Curcumin have been integrated through structural modifications of the molecule and new formulations.

Curcumin and cancer

Cancer is one of the major causes of increased death rates within developed countries. The early diagnosis and recommendation of the therapeutic options have reduced the death rate of the individuals. The growth of drug-resistant cancers evolves the integration towards developing effective drugs ^​23​. The tumor cells are characterized by deregulated signaling pathways involving proliferation, apoptosis, and angiogenesis ^​24​. Hence, Curcumin is considered an effective anticancer drug in this case while being utilized alone or in combination with other drugs. It tends to show mechanisms in the signaling pathways and molecular targets involved in developing different types of cancer.

Curcumin has shown efficacy and prevention against various types of cancer. Its other compounds prevent tumor formation and spread for tumor size reduction. It inhibits cancerous cells and metastasis of tumors by producing anti-angiogenic effects that result in apoptosis and interfere with the cell proliferation cycle ^​25,26​. 

Curcumin is a natural anti-cancer agent, is relatively considered as a clinical-based approach due to its inhibitory mechanism on the cancer cells. Curcumin is capable of inhibiting the signaling pathway in pancreatic cancer cells. It can hinder several other pathways related to breast cancer, colorectal cancer, pancreatic cancer, gastric cancer and ovarian cancer. It also modulates molecular targets involving transcription factors, kinases, inflammatory cytokines, growth factors and enzymes.

The human clinical studies proved that Curcumin is extremely safe even at very high doses. In phase I, clinical trials indicate that it is well-tolerated when Curcumin is taken as high as 12 g per day. It is not absorbed by the intestine and hence consumed with pepper or fat for increasing absorption rate. Therefore, it was recommended to consume turmeric supplements on an empty stomach, but in case the individual experiences any burning sensation within the gastric tract, they can consume it with food also. One of the studies revealed that Indian people have low rates of Alzheimer’s disease, as Indian cuisine consists of turmeric regularly.

Curcumin mechanism in cancer 

Curcumin exerts the mechanism of anticancer effects. Curcumin targets multiple pathways making it an extremely potent anticancer agent. The prolonged historical use of Curcumin in South Asian countries proves curcumin safety when consumed by any individual. Up to 12 g/day of curcumin intake demonstrates safety with no detrimental effects. Advantages of Curcumin on cancer were shown with inputs ranging from 100 mg/d-6 g/d in human clinical trials, while most of the studies represented advantages at dosages of approximately 2g/d–3 g/d.

Many concerns regarding the association of curcumin consumption with inhibition of certain drug-metabolizing enzymes, potential DNA damage, and iron chelation have been raised. Later, some reports suggest that preventing DNA damage by Curcumin and Curcumin’s reported role in iron chelation could be advantageous since a large amount of iron in cancer cells may increase the proliferation rate. Curcumin-free turmeric extracts have shown the inhibition of tumorigenesis induced by several agents. Cell culture studies are conducted that represented the fact that Curcumin alone possesses less potency in suppressing cancer growth when compared with turmeric consisting of a similar amount of Curcumin. Ryan et al. Examined the ability of oral Curcumin to reduce the severity of radiation dermatitis in 30 patients receiving radiation therapy for breast cancer.

The inhibition and suppression of cancer cell proliferation are integrated while exerting its effects on reducing modulation of anti-apoptotic gene products, activating caspase, and upregulating cancer-suppressive genes that include P53 ^{​27–29​}. Curcumin is capable of inducing tumor invasion by the reduction of modifying matrix metalloproteases (MMPs) that causes cell surface adhesion molecules such as NF-κβ, AP-1, TNF-α, LOX and COX-2, chemokines, growth factors (HER-2 and EGFR) to inhibit N-Terminal activity and tyrosine kinase protein ^​30,31​. It also inhibits angiogenesis in some of the tumors by suppressing angiogenic cytokines, including IL-6, IL-23, and IL-1β ^​32,33​.

The strong correlation between inflammation and cancer is represented in most cases that tend to evolve antitumor effects due to the anti-inflammatory effects of Curcumin. The other primary mechanism of anticancer effects of Curcumin is due to its interference in the cell cycle and reduction in CDK expression. CDKs are serine/threonine kinases that control cell cycle progression ^​34​.

Curcumin in Gastric Cancer

The action mechanism of Curcumin in gastric cancer ^​35​ is discussed below:

• Curcumin inhibits the proliferation and induction of gastric cancer cells.
• It can suppress multiple signaling pathways. 
• It inhibits cancer cell proliferation, invasion, and metastasis.
• It inhibits gastric cancer by minimizing proliferation rate, inducing apoptosis, and minimizing chemo-resistance of tumor cells.
• It downregulates the expression of factors causing apoptosis suppression and chemo-resistance.
• It downregulates the expression of factors causing apoptosis suppression and chemo-resistance.
• It induces apoptosis in gastric cancer cells.

Curcumin in Breast Cancer

Researchers prescribed tamoxifen with or without Curcumin 1200 mg/day three times in a study of breast cancer patients. In combination with Curcumin, people taking tamoxifen had about an 8% decrease in endoxifen (a chemical responsible for breast cancer development ) levels ^​36​. Many naturopathic oncologists caution that Curcumin is not consumed with certain drugs such as cyclophosphamide, anastrozole, exemestane, letrozole or erlotinib, or therapeutic doses of warfarin.

Curcumin in Colorectal Cancer

Colorectal cancer (CRC) is a malignant tumor bein the third most common cancer type worldwide. Certain curcumin analogues like C-5 curcumin analogue, curcumin diethyl succinate, bis-dihydroxy-curcumin and defluorinated-curcumin have drastically improved their efficacy chemo preventive and therapeutic compounds in colorectal cancer. 

The study represented that Curcumin reduces colorectal tumors and tumor size by exhibiting oxidative stress, altering homeostasis and tumor development ^​37​. Curcumin, when administered orally, undergoes fast metabolism within the intestine and liver while resulting in the excretion of 60-70% of the compound as faeces. Therefore, a heavy dose of Curcumin is needed for evolving therapeutic efforts. When combined with hyaluronic acid, Silica nanoparticles of Curcumin demonstrated significant reduction of the cell viability, increased uptake of Curcumin in intracellular cells, and enhanced efficiency against colorectal cancer.

Anticancer effects of Curcumin

The apoptosis induction and inhibition of cell proliferation and tumor invasion is regulated by suppressing the cellular signaling pathways. The antitumor mechanism in breast cancer, lung cancer, head and neck squamous cell carcinoma, prostate cancer, and brain tumors has targeted multiple cancer cell lines. Despite all the advantages of Curcumin, still, its application is limited to less solubility, which results in poor availability and lower chemical stability ^​38​. The cellular uptake of curcumin results in hydrophobicity that leads to curcumin penetration into the cell membrane and binding to the fatty acyl chains of membrane lipids through hydrogen bonding and hydrophobic interactions. As a result, low availability of Curcumin inside the cytoplasm is observed ^​39,40​. Hence, the improvement in the anticancer activity of Curcumin with various structural modifications is integrated for enhancing selective toxicity towards specific cancer cells, increasing bioavailability, and enhanced stability ^​41​. The anticancer activity of Curcumin is improved by utilizing different delivery systems showing efficacy in physicochemical properties. 

Clinical Evidence of Curcumin

Curcumin has shown significant efficacy due to its capability in therapeutics in terms of low toxic properties that implicate the fact that even if the consumed dose of 10 g/day does not offer any side effects . The high-dose consumption of Curcumin helps prevent the tumors from multiplying without causing any damage to the healthy cells ^​42​. The regulation of signaling pathways in cancer cells, minimizing the protein expression concerned with the drug resistance, and increasing the improvement in the antitumor drug development at different levels are the outcome of clinical studies done for Curcumin. It also reverses the drug resistance mechanisms and increases the sensitivity of chemotherapy-resistant cells. Hence, it is considered an effective chemical in cancer treatment ^​43​.

Minimal human clinical trials are being conducted on curcumin efficacy as anti-cancerous drugs. The information on the dosage, bioavailability, optimal signs, and potential toxicity is evaluated using large samples. The clinical studies have assessed the induction of autophagy, apoptosis, and cell cycle arrest for minimizing the survival and division of lung cancer cells. The human clinical trials depict its efficacy in Radiotherapy for lung cancer treatment by targeting different signaling pathways involving epidermal growth factor receptor and NF κB. Also, the clinical trials have evolved the use of Curcumin consisting of nanocarriers that shows efficacy in increasing the bioavailability, cell uptake, and curcumin antitumor activity ^​44,45​.

Very little limited clinical evidence has suggested the appropriate Curcumin effect in cancer treatment. Many studies have revealed the fact that Curcumin is effective in treating Colorectal Cancer. Some other clinical trials have been conducted amongst humans suggesting that Curcumin offers limited anticancer effects. Hence, their effectiveness depends individually based on the patient.

Curcumin decreased the disease markers in several studies, showing positive outcomes in prostate cancer, multiple myeloma, pancreatic cancer, and cervical neoplasia. In colorectal cancer, it enhanced the apoptotic cells relatively. It also showed a prominent response to Tumor Markers.

The oral Curcumin to the patients of adenomatous polyposis is recommended as per the efficacy of the clinical trials. One of the studies has shown administration of 1500 mg of oral Curcumin twice a day for 12 months to 44 patients with adenomatous polyposis. The results showed no significant difference between those receiving oral Curcumin and those receiving placebo ^​46​. The dosage of 100 and 300 mg/day of oral Curcumin is administered for evaluating the safety of Curcumin locally in patients with advanced or metastatic cancer. No change in tumor size was observed in this case ^​47​.

Using the histological diagnosis, another study has evaluated 24 patients aged 18 years suffering from metastatic colorectal cancer. The results showed the efficacy of curcumin administration as drugs to be safe and tolerable in chemotherapy ^​48​. Hence, the clinical evidence represents that Curcumin is used to inhibit and control cancer, improving the clinical symptoms and preventing metastasis by combining it with other drug formulations.

Lab evidence of Curcumin in different cancers

The efficacy of Curcumin for treating different types of cancer is evaluated from the clinical studies. Hence, the efficacy description is represented as below:

• Colorectal Cancer: In this type of cancer, a safe and efficient dose of a Curcumin supplement promoted colorectal liver metastases in many patients. It offers antitumor properties and anticancer effects, including anti-angiogenic ^​49​. Moreover, it finished the number and volume of animal tumors, promoted cell self-clearing, suppressed metastasis and angiogenesis, minimal multidrug dose-limiting toxicity and resistance, and balanced and relieved tumors in treatments of chemotherapy and radiation therapy.
• Breast Cancer: Curcumin represented a suppression of tumor metastasis and expansion, induced apoptosis of cancer cells when utilized as an adjunct therapy, improved oxaliplatin toxicity in the primary malignant cells, detected regressed tumor growth, and released tumor Pain and inflammation caused by treatments like Chemotherapy and Radiotherapy ^​50​.
• Prostate Cancer: In this type of cancer, Curcumin lowered cell proliferation, enhanced cell apoptosis, suppressed stem cell proliferation, reduced angiogenesis, and mitigated bone metastasis in androgen-independent and androgen-sensitive prostate cancer cells ^​51​.
• Ovarian Cancer: Curcumin showed limited anticancer effects on ovarian cancer. Some include enhanced sensitivity to cisplatin when utilized with quercetin induced cell apoptosis and other synergistic anticancer effects when combined with dihydroartemisinin ^​52​.
• Additional: Along with the effects mentioned above, Curcumin, when combined with 5-fluorouracil, mitigated the cancer growth in gastric carcinoma and also worked on cancers related to stomach, cervical, colorectal, head, uterine, neck, lung, oral, esophagus, pancreas, and bone ^​53​.

Furthermore, it was also efficacious in chemo sensitization and Radiotherapy sensitization

Benefits of Curcumin in cancer treatment

• Curcumin mitigated various side effects caused by painful cancer treatments, involving radiotherapy and chemotherapy. It, moreover, helped in protecting the human liver.
• Curcumin relatively lowered the criticality of Breast Cancer radiation dermatitis. However, more studies are needed to understand the benefits of Curcumin in treating breast cancer.
• A study was conducted among 160 cancer patients encountering cancer treatments like Radiotherapy and Chemotherapy. The study examined whether a reliable dose of Curcumin lowered symptoms like fatigue, nausea, diarrhoea, loss of appetite, insomnia, and much more. It is revealed that most of these symptoms in consuming Curcumin supplements are comparatively relived.
• Other severe symptoms related to Prostate Cancer were much milder on consuming Curcumin.
• Curcumin also lowered Depression levels in non-cancer patients.
• It enhanced body weight in several Colorectal Cancer patients undergoing cancer diagnosis.
• It enhanced body weight in several Colorectal Cancer patients undergoing cancer diagnosis.
• It decreased cholesterol levels in numerous patients prone to developing cardiovascular diseases.
• Curcumin enhances the quality of life in patients with critical tumors.
• It mitigated the risk of cachexia in patients suffering from Colorectal Cancer. 

Cautions with Curcumin

Curcumin is preferred as a secure supplement by the FDA. Several clinical trials have used up to 12 grams of Curcumin per day. Nonetheless, specific constituents in Curcumin can combine with iron, thereby lowering iron’s potentiality. It can be dangerous for people with iron deficiencies. It is highly recommended that you consult your doctor before using Curcumin for medical purposes. Some of the significant cautions are also adopted while using Curcumin.

• Mild and self-resolving gastrointestinal disturbances include loose stools, reflux, bloating and abdominal discomfort.
• It inhibited the synthesis of hepcidin (an iron-regulatory hormone), resulting in a drop in haemoglobin, causing anaemia-like conditions.
• A person with gallstones, bile duct dysfunction, hyperacidity, and stomach ulcers is not recommended to consume Curcumin.
• Pregnant and lactating females need to consult their doctors first before using curcumin supplements.
• Its extended use can cause heartburn and an upset stomach.
• If a person is undergoing any chemotherapy, do not take Curcumin without a physician’s advice. 
• Curcumin consumption should be restricted before surgery, as it can increase bleeding.

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References