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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 29  |  Issue : 2  |  Page : 115-118

Curcumin: Pharmacological actions and its role in head and neck squamous cell carcinoma - A review


1 Department of Oral Medicine and Radiology, Sarjug Dental College and Hospital, Darbhanga, Bihar, India
2 Department of Psychiatry, Sri Krishna Medical College and Hospital, Muzaffarpur, Bihar, India
3 Department of Public Health Dentistry, Institute of Dental Sciences, Bareilly, Uttar Pradesh, India
4 Department of Oral Pathology and Microbiology, Sarjug Dental College and Hospital, Darbhanga, Bihar, India

Date of Submission14-Aug-2016
Date of Acceptance25-Oct-2017
Date of Web Publication9-Nov-2017

Correspondence Address:
Abhijeet Alok
Department of Oral Medicine and Radiology, Sarjug Dental College and Hospital, Hospital Road, Laheriasarai, Darbhanga - 846 003, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.JIAOMR_100_16

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   Abstract 

Curcumin is derived from turmeric and has a variety of therapeutic properties. Various research on curcumin have showed that it also exhibits anti-cancer properties. It is known to act on tumor cells via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis, and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor nuclear factor kappa B (NF-Kb) and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-a, interleukins and MMP-9). Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck squamous cell carcinoma (HNSCC) as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent.

Keywords: Anticancer, antioxidant, curcumin, head and neck squamous cell carcinoma


How to cite this article:
Alok A, Singh ID, Singh S, Jha A. Curcumin: Pharmacological actions and its role in head and neck squamous cell carcinoma - A review. J Indian Acad Oral Med Radiol 2017;29:115-8

How to cite this URL:
Alok A, Singh ID, Singh S, Jha A. Curcumin: Pharmacological actions and its role in head and neck squamous cell carcinoma - A review. J Indian Acad Oral Med Radiol [serial online] 2017 [cited 2020 Dec 5];29:115-8. Available from: https://www.jiaomr.in/text.asp?2017/29/2/115/217902


   Introduction Top


Cancer remains one of the most complex diseases affecting worldwide populations. Oral cancer is third leading cause of death in developed countries.[1] It is projected that the number of new cases of all cancers worldwide will be 15.4 million in the year 2020.[2] The development of head and neck squamous cell carcinoma (HNSCC) is strongly associated with certain risk factors, for example, consumption of alcohol and tobacco. In addition to these risk factors, exposures to epstein barr virus and human papilloma virus infection acts as causative agent in development of HNSCC in such patients who do not have histories of alcohol or tobacco usage.[3],[4]

Standard treatment regimens for HNSCC depend on the stage of the disease. Early stage (Stage I and II) tumors are treated primarily with surgery or radiotherapy. Surgery or radiation is used with curative intent in the treatment of oral cancer. Chemotherapy is an adjunct to the principal therapeutic modalities of radiation and surgery. For advanced stages, chemotherapy is used in combination with either or both of the early or primary treatment modalities.[5] In localised HNSCC, where surgical removal of disease can result in unacceptable loss of function for patient, concurrent chemoradiation is the preferred treatment. Platinum-based agents form the backbone of the standard chemotherapeutic regimens for HNSCC. The principal agents that have been studied alone or in combination are methotrexate, bleomycin, taxol and its derivatives, platinum derivatives, cisplatin (cis-diammined ichloroplatinum), which also includes carboplatin and oxaliplatin, and 5-fluorouracil.[6] The potential adverse effects of the treatment for HNSCC are numerous.

Most anti-cancer drugs are expensive with serious side effects. It is ideal to find a treatment without side effects. Need of the hour is to have a drug with strong therapeutic potential and also minimal side effects and which can target multiple molecular and cellular pathways in cancer. Derived from turmeric (Curcumin longa), curcumin is one such agent. From ancient times, it has been used as a healing agent for variety of illnesses. Curcumin has got anti-cancer properties. It inhibits the proliferation of cancer cellsin vitro and in vivo, induces apoptosis, and inhibits angiogenesis.


   Curcumin Top


Curcumin (diferuloylmethane) is a polyphenol compound found in south Asia.[7],[8] Previous pharmacological studies have demonstrated that curcumin exhibit properties like antioxidant, analgesic, anti-inflammatory, antiseptic activity, anti-carcinogenic activity, chemopreventive, chemotherapeutic activity, anti-tumor, anti infective properties (against virus, bacteria, and fungus), and anti-platelet activity.[9],[10]

Thus, it shows a big promise as a therapeutic drug.In vivo trials of curcumin are extensively going on worldwide in persons suffering from either of diseases like multiple myeloma, pancreatic cancer, colon cancer, mastitis myelodysplastic syndromes, psoriasis, diabetic nephropathy, periodontal disease, HNSCC, canker sore, precancerous lesion, etc.[11] To develop curcumin into a preventive or therapeutic drug, it is important to consider the dose levels that elicit desirable effects.


   Anti-Cancer Properties of Curcumin Top


Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of body. Spreading of cancer cells is a process that often leads to changes in morphology and in cellular behaviour. Cancer cells in body targets specific site for their progression. Over years, it has been found that curcumin targets these specific sites of cancer cells, thus regulating the survival or death of cancer cells. Pre-clinical studies in a variety of cancer cells have consistently shown that curcumin possesses anti-cancer activityin vitro and in preclinical animal models. As compared to other anti-cancer drugs, curcumin shows anti-cancer effects at lower doses. The anti-cancer properties of curcumin are due to its properties of inhibition of tumor initiation and tumor promotion.[12]

Antioxidant activity

Synthetic non-phenolic curcuminoids exhibited no antioxidant activity; therefore, curcumin is a classical phenolic chain-breaking antioxidant. It has shown to possess antioxidant property. It acts as a free radical scavenger and interferes with lipid peroxidation and forms a fatty acid radical.[13] Curcumin acts as a chain-breaking antioxidant at the 3′ position, resulting in an intramolecular Diels-Alder reaction and neutralization of the lipid radicals.[14] In various studies conducted on rat, it has been shown that curcumin scavenge various reactive oxygen species produced by macrophages.[15] It has also been found that curcumin downregulates inducible nitric oxide synthase in macrophages, thus reducing the amount of reactive oxygen species generated as a response to oxidative stress.

Anti-inflammatory activity: Effect on NF-κb pathway

Nuclear Factor-kappa B (NF-kB) is an ubiquitous eukaryotic transcription factor, and is involved in regulation of inflammation, cellular proliferation, transformation, and tumorigenesis. On activation by free radicals, inflammatory stimuli, cytokines, carcinogens, tumor promoters, endotoxins, gamma-radiation, ultraviolet (UV) light, or X-rays, NF-kB is increased in many cancers, and is associated with various steps in the development of malignancy such as expression of anti-apoptotic genes, angiogenesis, tumor promotion, and metastasis.[16] Several authors have stated that activated NF-kB suppresses apoptosis in a wide variety of tumor cells and it has been implicated in chemoresistance. Furthermore, the constitutively active form of NF-kB has been reported in human breast cancer, pancreatic cancer, HNSCC, multiple myeloma, mantle cell lymphoma, and melanoma.[17]

Curcumin's inhibitory effect on the NF-kB pathway is central to providing the compound with its anti-inflammatory properties. It blocks the inhibitory kappa B kinase (IkK) - mediated phosphorylation and degredation of IkBa, thus NF-kB remains bound to IkBa in the cytoplasm and is not able to enter the nucleus to activate transcription. In addition to inhibiting NF-kB activation, curcumin also has suppressive effects on other pathways involved in inflammation.[18]

Anti-cancer activity: Suppression of carcinogenesis

Carcinogenesis is a genetic process that leads to a change in morphology and in cellular behaviour. The assessment of molecular change may become the primary means of diagnosis and may guide the management of cancer. Major genes involved in HNSCC include proto-oncogenes and tumor suppressor genes. Other factors that play a role in the progression of disease may include the allelic loss at other chromosome regions, mutations to proto-oncogenes and tumor suppressor genes, or epigenetic changes such as deoxyribonucleic acid methylation or histone deacetylation. The chemotherapeutic and chemopreventive properties of curcumin are due to its ability to target different phases of cell growth, which are targeted by tumor cells. In addition to this, curcumin also acts on transcription factors, oncogenes, stages of carcinogenesis.

It also has the ability to suppress UV irradiation-induced DNA mutagenesis and induction of cellular SOS functions.[19] Curcumin's antioxidant property plays a major role in its inhibiting carcinogenesis. Curcumin scavenges DNA-damaging superoxide radicals. It also affects both the Phase I and Phase II enzymes of the hepatic cytochrome p450 enzyme system involved in the oxidation and detoxification of toxic substances. In phase I, curcumin has inhibitory effect on enzymes, whereas in phase II, curcumin induces enzymes who plays a role in detoxification of toxic metabolites.[20],[21] In various researches on animals, curcumin has demonstrated its chemopreventive and chemotherapeutic properties.

Effect on cell cycle regulation and apoptosis

Cancer is basically a disease of uncontrolled cell division. Any aberrations in normal cellular growth and proliferation lead to malignant phenotype of tumor cells. In tumor cells, growth and proliferation of cell cycles remain unchecked. In cancers affecting hematology and solid tumors, cyclin D1 overexpression has been found to be a major factor in progression of cancer.[22],[23] Curcumin suppresses the expression of cyclin D1 in cancers including HNSCC, colon, bladder, breast, cervical, and pancreatic carcinomas, an effect that is attributed to curcumin's inhibition of NF-kB activation and subsequent suppression of downstream gene products.[24]

Understanding the mechanism of apoptosis is vital in the development of drugs that target certain apoptotic genes or pathways. Caspases are central to the mechanism of apoptosis as they are both initiators and executioners. There are three apoptotic pathways, the intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway and the third one is intrinsic endoplasmic reticulum pathway. Apoptosis in normal cell is guided by cell death receptors, CD95, resulting in DNA damage. Besides, there is role of some other pro-apoptotic factors (BAD, BAX, BID, and TP53) and apoptosis inhibitors (BCL2, BCL-X). The intrinsic pathway involves TP53 functioning as a transcription factor to upregulate the expression of Bax. Bax is a pro-apoptotic protein that antagonizes Bcl-2, which is present in the mitochondrial membrane.[25] In cancer cells, the function of apoptosis is interfered due to mutations in genes, which regulate apoptosis in the normal cells. Curcumin has the property of inducing apoptosis in tumor cells at the cell cycle phase G2. It induces apoptosis via upregulation of p53 expression and initiation of the mitochondrial apoptotic pathway via increased Bax expression and cytochrome c release.[26] Curcumin has a stimulatory effect on the extrinsic apoptotic pathway, which is triggered by the binding of “death activators” such as TNF-a, and Fas Ligand to their corresponding cell surface receptors.[27] Curcumin's suppression of the NF-kB-mediated cell survival pathway is also important in the compound's pro-apoptotic effect.

Effects on autophagic process

Autophagy is a process by which worn out intracellular organelles and other cytoplasmic material form autophagic vacuole that fuses with lysosome to form autophagolysosome. This process is an important cellular response to stress or starvation. Autophagy helps cells to recycle endogenous biosynthetic substrates such as amino acids.[28] Many studies have shed light on the importance of autophagy in cancer development, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. Autophagy has also been found in mediating chemotherapeutic resistance along with cell death. Curcumin has been found to arrest G2/M phase of cell cycle and non-apoptotic autophagic cell death. It is also found to inhibit tumor growth significantly.

Effects on angiogenesis and metastasis

New growth in the vascular network is important since the proliferation, as well as metastatic spread of cancer cells depends on vascular channels, i.e., blood and lymphatic vessels. Angiogenesis is regulated by both activator and inhibitor molecules. The cancer cells without blood circulation grow at slower pace or even growth is stopped due to lack of blood circulation compared to when placed in area where angiogenesis is possible. Angiogenesis is important for progression of cancer.[29],[30] Curcumin has shown anti-angiogenic effect and also has been shown to regulate a variety of pro-angiogenic growth factors, enzymes, and transcription factors. It also reduces angiogenic biomarkers. In addition to all this, curcumin affects a number of cell adhesion molecules.[31]


   Evidence Based Role of Curcumin in Head and Neck Squamous Cell Carcinoma Top


Curcumin has been studied worldwide in variousin vivo andin vitro model of HNSCC. In a study conducted by Dudas et al., he showed that curcumin targets fibroblast-tumor cell interactions in oral squamous cell carcinoma.[32] In another study conducted by Maria M. LoTempio et al., it was found that administration of curcumin in a dose-dependent fashion lead to growth inhibition of HNSCC cell lines bothin vivo andin vitro.[33] Oral mucositis, one of the most common side effects of radiotherapy, can be treated when gargled with turmeric. They significantly delay and reduce the severity of mucositis.[34]


   Adjuvant Therapies under Investigations in Head and Neck Squamous Cell Carcinoma Top


In addition to curcumin, several molecular targeted agents are currently being explored in HNSCC. The anti-EGFR monoclonal antibody cetuximab, tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib), anti-vascular endothelial growth factor receptor, bortezomib in combination with docetaxel etc., are studied worldwide as adjuvant therapy in HNSCC [Table 1].
Table 1: Adjuvant therapies under investigation in HNSCC

Click here to view



   Conclusion Top


Introduction of curcumin as an anti-cancer drug has been a boon in the field of medicine. Through various clinical trials on humans, curcumin has been found to be safe with minimal side effects. It can kill a wide variety of tumor cell types through diverse mechanisms; it is possible that cells may not develop resistance to curcumin-induced cell death. In addition, curcumin only kills the specific tumor cells and spares the normal cells. This property of curcumin makes it an attractive candidate for drug development. Several factors need to be evaluated, investigated, and developed but the prospects for curcumin as a therapeutic agent are indeed promising.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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