C. longa or zerdeçal, is also known as turmeric in English-speaking countries, jiang huang in eastern countries, and curcuma or saffron in latin-speaking countries. Belonging to the family Zingiberaceae, turmeric is herbaceous plant, perennial that present large and long leaves and ovoid rhizomes. It is native to India and southeast of Asia, but it is spread throughout Europe and America.

The turmeric anticancer activity was evidenced by the ability to induce apoptosis (Table 1) [7-16], inhibit proliferation of different tumor types and favor metastasis reduction (Table 2) [17-27].

Inhibitory effect against angiogenesis, growth factor receptors and cell adhesion molecules involved in tumor growth was associated to the potential to reduce metastasis. Curcuminoid compounds such as demethoxycurcumin, bisdemethoxycurcumin, and tetrahydrocurcumin were isolated from turmeric root. Among the commonly isolated curcuminoids, curcumin is the most abundant, highlighting that 13 curcuminoids with anticancer activity were described [28].

Comparing the cell growth inhibition effect by pure curcumin and turmeric methanolic extract, it was presented much more effective inhibition by curcumin (half maximal inhibitory concentration (IC50) = 41.69 ± 2.87 μg mL-1) than the turmeric methanolic extract (IC50 = 196.12 ± 5.25 μg mL-1) [15]. But factors such as tumor type [7,29,30] and dose-time-dependent action [7,27,30-32] appear to interfere in anticancer activity.

Curcumin (2 μM) decreased mesenchymal cell proliferation while cell death was detected only at 50 μM. Highly migratory cells decrease on migration speed and directionality about 50% and 40% when treated with 2 or 5 μM of curcumin, respectively. In addition, the curcumin decreased cell adhesion with dose dependence, especially on tumor-derived spheroids [27].

Although the curcumin antitumor activity has been demonstrated to be important, in the same way the antitumor effect of turmeric has also been observed both in the form of extracts [23,33,34] and essential oil [14].

Studies that evaluated curcumin-free turmeric observed suppression of benzo[a] pyrene-induced tumorigenesis in mice [33] and inhibition of 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats [34]. Antiproliferative activity between curcumin and turmeric was compared in seven cancer cell lines. Both treatments presented similar amounts of curcumin, with a higher inhibition percentage for turmeric in all cell lines tested [23]. Therefore, other components than curcumin also contribute to the turmeric anticancer activities.

Curzerene is a sesquiterpene that presented dose-dependent antiproliferative effect both in vitro and in vivo test [32]. The crude turmeric methanolic extract was evaluated by gas chromatography-mass spectrometry analysis (GC-MS). 50 compounds were detected, and the major compounds were ar-turmerone (20.50%), β-sesquiphellandrene (5.20%) and curcumenol (5.11%) [15]. Recently evaluating turmeric ethanolic extract, four new sesquiterpenes were isolated [35].

Concerning the form of essential oil obtained from rhizomes, sesquiterpenes and oxygenated monoterpenes such as ar-Turmerone (33.2%), α-Turmerone (23.5%) and β-Turmerone (22.7%) were recorded using CG-MS and nuclear magnetic resonance (NMR) spectroscopy [14].

Likewise, using GC-MS to evaluate the essential oil, turmerone (35.9%) was the majority component among the 23 compounds identified [36]. Complementarily, it should be noted that beyond the direct antineoplastic effects, the indirect effects such as immunomodulatory and anti-inflammatory activities are relevant for tumor therapy (Table 3) [37-40].

Pre-clinical and clinical assays also demonstrated promising results (Table 4) [41-49]. But, although these tests were performed in mice, rats, dogs and other experimental animals, the development of research directly for veterinary medicine is scarce.

The combination of curcumin and cisplatin in the treatment of lung adenocarcinoma cells (A549) was favorable due to reversing tumor resistance. It was demonstrated (in vitro) the inhibition of factor induced by hypoxia-1 (FIH-α) and reduction of P-glycoprotein, these proteins are related to tumor resistance [50]. Furthermore, curcumin reduced neurotoxicity [51] and cisplastin nephrotoxicity [52].

The use associated with radiotherapy indicated that curcumin favored the action of radiation on colon cancer cells (HCT116 and HT29), increased sensitivity to this type of treatment by inhibiting nuclear factor kappa B (NF-κB) [47].

Promising results were found regards the effect of curcumin as a sensitizing agent to enhance the apoptotic potential of doxorubicin [31]. These researchers evaluated IC50 dose (5 nM) of doxorubicin and a lower dose (2.5 nM). They found that both curcumin (10 μM) and doxorubicin (5 nM) induced apoptosis. However, the association of curcumin (10 μM) with doxorubicin at a lower dose than its IC50 (2.5 nM) was able to induce a higher level of apoptosis in Pre-B acute lymphoblastic leukemia cell lines. It was also observed dose dependence which suggests enhanced level of apoptosis when curcumin was supplemented with doxorubicin in cell culture.

Unfortunately, unfavorable associations may occur mainly if high doses of curcumin are used. It was verified that 6000 mg of curcumin per day represent the limit dose capable to induce adverse effects. Higher doses (8000 mg daily) demonstrated to affect negatively the association with docetaxel in breast cancer [42]. The same association was studied in MCF7 and MDA-MB-231 breast cancer cells [29]. Curcumin at 10 mg L-1 in cotreatment with docetaxel induced modifications in glutathione and lipid metabolisms and glucose utilization. Some of these changes were biphasic depending on the exposure duration to curcumin. Thus, the continuity of research involving the use of curcumin to cancer treatment is increasingly justified. Despite the various publications in recent years, the mechanisms of action involved still need to be best clarifying, mainly when combining two active principles [29].

The association between medicinal plants may also determine benefits to oncological treatment. Curcumin associated with Zingiber officinale promoted growth inhibition of prostate cancer and presented superior results when compared to both treatments [53,54].

One of the major obstacles to the success of chemotherapy is the fact that some tumor cells develop multidrug pharmacological resistance (MDR) [55]. This process may be associated with overexpression of efflux pumps drug. P-glycoprotein is a drug efflux pump that is often found to be overexpressed in cases of acquired MDR. However, there are no P-glycoprotein inhibitors used in current clinical practice due to toxicity problems, drug interactions or pharmacokinetic problems. Thus, it has been carried out to search for natural products that can inhibit glycoproteins such as P-glycoprotein. Curcumin has shown important inhibition [56,57], emerging as a potential drug for the antitumor treatment response.

The high metabolism and low half-life of curcumin impairs its absorption when administered orally [17,26,41,44,45,56]. Therefore, in order to increase the solubility, bioavailability and anticancer activity of curcumin, associations with liposomes [17,26,44,45], nanoparticles [43,58] and mainly piperine [59,60] have been proposed.

The incorporation of curcumin into liposomes promoted growth inhibition of pancreatic carcinoma cell lines [17]. Similarly, liposomal curcumin suppresses the growth of head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and UM-SCC1 in vitro and in vivo tests [26]. Association between curcumin and liposomes was also evaluated from intravenous infusion of 10 mg Kg-1 in dogs [44]. These results indicated high plasma concentration of curcumin two hours after infusion, suggesting that this combination may be used in plasma cell and multiple myeloma tumors. This study was also performed by Matabudul, et al. [45] and after eight hours of infusion it was observed a significant increase of curcumin in lung, spleen and liver, demonstrating that the infusion time determined a better distribution of curcumin.

The nanoparticles associated with curcumin favor physical stability with maintenance of the cytotoxic activity of this curcuminoid in cancerous cells [43,54,56].

By intravenous administration (2.5 mg Kg-1) in mice, this association increased the bioavailability of curcumin in almost two times [56]. These authors also confirmed the antiproliferative activity in human chronic myeloid leukemia (KBM-5), human T-cell leukemia (Jurkat), prostate cancer cells (DU145), breast tumor (MDA-MB-231), esophageal cancer (SEG-1) and colon cancer (line HCT116). It was demonstrated that curcumin loaded nanoparticulate formulation based on poly lactide-co-glycolide (PLGA) has enhanced cellular uptake and increased bioactivity in vitro and superior bioavailability in vivo over curcumin. They also observed increased cellular uptake of curcumin and inhibition of nuclear factor- kappa B (NF-κB) expression level.

Rats submitted to curcumin with nanoparticles by the oral route demonstrated increased solubility and bioavailability in five to six times and had a longer half-life. The results showed that the effect in improving oral bioavailability of curcumin may be associated with improved water solubility, higher release rate in the intestinal juice, enhanced absorption by improved permeability, inhibition of P-glycoprotein-mediated efflux and increased residence time in the intestinal cavity [43].

The association of curcumin with piperine, a polyphenol isolated from black peppers, increased the curcumin oral bioavailability [58,61]. In order to determine the ability to modulate the self-renewal of normal and malignant breast cells, Kakarala, et al. [58,61,62] examined multiple spheres formation trait and the expression of the breast stem cells with aldehyde marker dehydrogenase (ALDH) signaled by Wnt pathway. Both curcumin and piperine were able to inhibit the formation of the multiple beads, however, the addition of piperine to curcumin potentiated this reduction compared to the compounds used separately (Figure 1).

In addition, it is important to consider that some compounds of piperine may be able to determine some synergic action mechanism with turmeric. Genotoxicity was evaluated in hamsters induced by single dose (30 mg Kg-1) intraperitoneal injection of 7,12-dimethylbenz[a]anthracene. The curcumin association with piperine was able to potentiate its antigenotoxic effect, evidenced by the decrease of polychromatic erythrocytes and acrosomal aberrations [61,62].

Considering the antitumoral effect of β-elemene derived from Curcuma wenyujin, it was synthesized five novel β-elements from the piperazine: 13-(3-methyl-1-piperazinyl)-b-elemene (DX1), 13-(cis-3,5-dimethyl-1-piperazinyl)-b (DX2), 13-(4-isopropyl-1-piperazinyl)-b-eel (DX4) and 13-piperazinyl-b-element (DX5) [7]. These researchers reported that activation of caspase-8 by these new β-elemene, piperazine derivatives, was correlated with the decrease of cellular FLICE-like inhibitory protein (c-FLIP) levels and H2O2 production, which determined the activation of the apoptotic pathways mediated by mitochondria, suggesting the influence of a synergic action mechanism.