Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma

Abstract

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities 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 NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. 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 cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent.

Figure 1

Structure of the curcuminoids curcumin, demethoxycurcumin and bisdemethoxycurcumin.

Figure 2

Overview of the anti-cancer effects of curcumin. Curcumin suppresses the activation of NF-κB via inhibition of IκKB activity, leading to suppression of many NF-κB-regulated genes involved in tumorigenesis including TNF,COX-2, cyclin D1, c-myc, MMP-9 and interleukins. Curcumin is involved in cell cycle control and stimulation of apoptosis via upregulation of p16 and p53. In addition, curcumin is a modulator of autophagy and has inhibitory effects on tumor angiogenesis and metastasis via suppression of a variety of growth factors including VEGF, COX-2, MMPs and ICAMs.

Figure 3

Cell cycle regulation by Rb and p53 tumor suppressor proteins. A) Inactivation of Rb and p53 proteins occurs by phosphorylation for the progression of the cell cycle from the G1 to the S phase. Kinase function of CDK4 is activated by cyclin D1 and inactivated by p16 proteins. Cyclin E and p21 control the activation and inactivation of CDK2, respectively. Ubiquitination of p53 takes place by complexing with MDM2 that is blocked by p14ARF (ARF, alternative reading frame). B) Inactivation of p16 by deletion, methylation, or mutation and/or by amplified expression of cyclin D1 leads to increased phosphorylation of Rb resulting in the activation of E2F mediated transcription. However, increased expression of p16 and reduced expression of cyclin D1 results in hypophosphorylated Rb binding to E2F transcription factor leading to the inactivation of transcription.

Figure 4

Programmed cell death type I: Apoptosis: In response to cellular damage, activation of p53 results in increased expression of Bax and antagonism of the anti-apoptotic protein Bcl-2. As a result, mitochondrial membrane permeability increases and cytochrome C is released into the cytosol. Cytochrome C binds Apaf-1 to form an apoptosome complex leading to activation of caspase-9 and initiation of the caspase cascade and resultant cell death.

Figure 5

Programmed cell death type II: Autophagy is a catabolic process by which cells degrade their own components via the lysosomal system. In response to cellular or nutrient stress, double-layered autophagosomes containing cytoplasmic proteins and organelles are formed following envelopment by a membrane derived from the endoplasmic reticulum. Upon fusion with lysosomes, the contents of these autophagolysosomes are degraded. Autophagy is important as a housekeeping function to promote cell survival and may also function as a pathway of programmed cell death.