**Anticancer Properties of Curcumin**

Varisa Pongrakhananon1,2 and Yon Rojanasakul2

*1Chulalongkorn University, Department of Pharmacology and Physiology Faculty of Pharmaceutical Sciences, Bangkok, 2West Virginia University Department of Basic Pharmaceutical Sciences, Morgantown, West Virginia 1Thailand 2USA* 

### **1. Introduction**

Curcumin is a major biological active compound from turmeric or *Curcuma longa*. This nontoxic natural compound has been reported to possess several biological activities that are therapeutically beneficial to cancer treatment. It has been reported to increase the efficacy of other chemotherapeutic agents and to reduce their toxic side effects which are the major drawback of most chemotherapeutic agents. Curcumin is also well known for its antiinflammatory activity (Amanda and Robert, 2008). Since cancer often develops under chronic inflammatory conditions, curcumin has the potential to be a preventive treatment agent against cancer. Furthermore, unlike most chemotherapeutic agents which act on a specific process of cancer development, i.e., cell growth or apoptosis, curcumin exerts its effect on various stages of cancer development, i.e., oncogene activation (Singh and Singh, 2009), cancer cell proliferation (Simon et al., 1998), apoptosis evasion (Han et al., 1999), anoikis resistance (Pongrakhananon et al., 2010), and metastasis (Chen et al., 2008) (Figure 1). Therefore, curcumin has the potential to overcome chemoresistance which is a major problem in cancer chemotherapy. This chapter will provide an overview of the anticancer activities of curcumin and present pre-clinical and clinical evidence supporting the use of curcumin as an anticancer agent.

Cancer is known to be associated with genetic instability in which *c-myc* serves as a major modifier of many targeted genes (Mai and Mushinski, 2003). Likewise, the mutation of proto-oncogene *ras* has been identified in many types of tumor (Rajalingam et al., 2007). The dysregulation of these oncogenes is well recognized as an initial step in the development of tumorigenesis. Interestingly, curcumin has been reported to have a suppressive effect on the oncogenes and inhibit their downstream effectors such as cell cycle promoting and proapoptotic proteins (Singh and Singh, 2009). Curcumin also exhibits anticancer properties through its ability to inhibit cell proliferation and induce apoptosis. The anti-proliferative effect of curcumin is dependent on its concentration, duration of treatment, and specific cell type. At low doses, curcumin causes cell cycle arrest, while at higher doses it induces apoptosis. Cell proliferation is controlled by several cell cycle regulating proteins, notably the family of cyclin and cyclin-dependent kinases (Kastan and Bartek, 2004) whose expression is tightly associated with tumorigenesis (Diehl, 2002). Curcumin inhibits cell cycle progression by downregulating cyclin D1 and the transition from G1 to S phase in

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secondary tumors. A recent study by our group has shown that curcumin is able to sensitize lung cancer cells to undergo anoikis through a mechanism that involves post-translational modification of Bcl-2 via the ubiquitin-proteasome pathway (Pongrakhananon et al., 2010). Curcumin also acts as a negative regulator of cancer cell migration and invasion through diverse signaling pathways including MMP-9, MMP-2 and COX-2 (Philip et al., 2004, Lee et

Animal and clinical studies of curcumin have been well investigated. In mice, curcumin markedly inhibits DMBA and TPA-induced skin tumor formation (Azuine et al., 1992). In a xenograft model, curcumin administration significantly decreases the incidence of breast cancer metastasis to the lung (Aggarwal et al., 2005). In phase 1 clinical studies, oral administration of curcumin was shown to be well tolerated with no dose-limiting toxicity (Sharma et al., 2004; Lao et al., 2006). In patients with intestinal metaplasia, curcumin treatment showed a significant improvement in the precancerous lesion (Cheng et al., 2001), supporting the clinical use of curcumin as a preventive treatment agent against cancer. Although curcumin has demonstrated promising pharmacological effects and safety both *in vitro* and *in vivo*, poor bioavailability and tissue accumulation have been observed with the compound. Further studies on proper drug delivery, dose optimization, and biodistribution

For thousands of years, plants and some parts of animal have been used as dietary agents which have been identified to be biologically active. These natural compounds have gained considerable interest for their potential as treatment and preventive agents for human diseases. Curcumin (diferuloylmethane) is a major biologically active compound extracted from the dried rhizome of turmeric or *Curcuma longa*. It has been widely used for centuries as medicinal plant and food additive due to its yellow color. Its medicinal properties are attributed to curcuminoids, which include curcumin (curcumin I), demethoxycurcumin (curcumin II), and bisdemethoxycurcumin (curcumin III) (Figure 2). Curcumin I (77%) is a

major component found in commercial curcumin, while curcumin II and III constitute approximately 17% and 3% respectively. Cucumin is a water-insoluble compound, but

al., 2005; Hong et al., 2006; Lin et al., 2009).

are needed.

**2. Chemistry of curcumin** 

Fig. 2. Chemical structure of curcuminoids

human head and neck squamous carcinoma cells (Aggarwal et al., 2004). It also inhibits bladder cancer cell proliferation through the downregulation of cyclin A and upregulation of p21 (Park et al., 2006).

Fig. 1. Anticancer properties of curcumin

Curcumin possesses apoptosis-inducing activity causing cancer cell death primarily through the mitochondrial death pathway. It induces an upregulation of the proapoptotic protein Bax and downregulation of the antiapoptotic protein Bcl-2 in breast cancer cells (Chiu and Su, 2009), resulting in the loss of mitochondrial function, release of cytochrome c, and activation of caspase-9 and -3 (Chen et al., 2010). Curcumin also potentiates the cytotoxic effect of chemotherapeutic agents such as cisplatin (Chanvorachote et al., 2009), doxorubicin (Notarbartolo et al., 2005), tamoxifen (Chuang et al., 2002), and placitaxel (Genta and Amiji, 2009). The use of curcumin as a chemo-sensitizing agent in combination therapy has the potential to overcome chemoresistance which is common in advance staged cancers and is a major cause of cancer-related death.

An increasing number of reports have described the inhibitory effect of curcumin on cancer metastasis. Metastasis is a multi-step process involving tumor vascularization, cancer cell detachment, avoidance of anoikis, and increased cell invasion. The vascularization induced by tumor is an essential step providing nutrients, oxygen, and removing waste products for tumor growth and metastasis. A key mechanism that cancer cells utilize during metastasis is the acquisition of anoikis resistance. Anoikis or detachment-induced apoptosis is recognized as an important mechanism preventing cancer cell dissemination and invasion to form

human head and neck squamous carcinoma cells (Aggarwal et al., 2004). It also inhibits bladder cancer cell proliferation through the downregulation of cyclin A and upregulation

Curcumin possesses apoptosis-inducing activity causing cancer cell death primarily through the mitochondrial death pathway. It induces an upregulation of the proapoptotic protein Bax and downregulation of the antiapoptotic protein Bcl-2 in breast cancer cells (Chiu and Su, 2009), resulting in the loss of mitochondrial function, release of cytochrome c, and activation of caspase-9 and -3 (Chen et al., 2010). Curcumin also potentiates the cytotoxic effect of chemotherapeutic agents such as cisplatin (Chanvorachote et al., 2009), doxorubicin (Notarbartolo et al., 2005), tamoxifen (Chuang et al., 2002), and placitaxel (Genta and Amiji, 2009). The use of curcumin as a chemo-sensitizing agent in combination therapy has the potential to overcome chemoresistance which is common in advance staged cancers and is a

An increasing number of reports have described the inhibitory effect of curcumin on cancer metastasis. Metastasis is a multi-step process involving tumor vascularization, cancer cell detachment, avoidance of anoikis, and increased cell invasion. The vascularization induced by tumor is an essential step providing nutrients, oxygen, and removing waste products for tumor growth and metastasis. A key mechanism that cancer cells utilize during metastasis is the acquisition of anoikis resistance. Anoikis or detachment-induced apoptosis is recognized as an important mechanism preventing cancer cell dissemination and invasion to form

of p21 (Park et al., 2006).

Fig. 1. Anticancer properties of curcumin

major cause of cancer-related death.

secondary tumors. A recent study by our group has shown that curcumin is able to sensitize lung cancer cells to undergo anoikis through a mechanism that involves post-translational modification of Bcl-2 via the ubiquitin-proteasome pathway (Pongrakhananon et al., 2010). Curcumin also acts as a negative regulator of cancer cell migration and invasion through diverse signaling pathways including MMP-9, MMP-2 and COX-2 (Philip et al., 2004, Lee et al., 2005; Hong et al., 2006; Lin et al., 2009).

Animal and clinical studies of curcumin have been well investigated. In mice, curcumin markedly inhibits DMBA and TPA-induced skin tumor formation (Azuine et al., 1992). In a xenograft model, curcumin administration significantly decreases the incidence of breast cancer metastasis to the lung (Aggarwal et al., 2005). In phase 1 clinical studies, oral administration of curcumin was shown to be well tolerated with no dose-limiting toxicity (Sharma et al., 2004; Lao et al., 2006). In patients with intestinal metaplasia, curcumin treatment showed a significant improvement in the precancerous lesion (Cheng et al., 2001), supporting the clinical use of curcumin as a preventive treatment agent against cancer. Although curcumin has demonstrated promising pharmacological effects and safety both *in vitro* and *in vivo*, poor bioavailability and tissue accumulation have been observed with the compound. Further studies on proper drug delivery, dose optimization, and biodistribution are needed.
