Anticancer Effects

The anticancer potential of curcumin has been demonstrated in various in vitro and in vivo models [40]. Curcumin has been shown to block transformation, tumor initiation, tumor promotion, invasion, angiogenesis, and metastasis. In in vivo studies, curcumin suppressed carcinogenesis of the skin, forestomach, colon, and liver in mice. Curcumin has been shown to inhibit proliferation of a wide variety of tumor cells, including B-cell and T-cell leukemias [41-44], colon carcinoma [45], epidermoid carcinoma [17], head and neck squamous cell carcinoma [46], multiple

Fig. 7.1 Traditional Uses of Curcumin

myeloma [20], and mantle cell lymphoma [36]. It has also been shown to suppress proliferation of various breast carcinoma cell lines in culture [47-49].

Mehta et al. examined the antiproliferative effects of curcumin against several breast tumor cell lines, including hormone-dependent and -independent and multidrug-resistant lines [47]. All the cell lines tested, including the multidrug-resistant ones, were highly sensitive to curcumin. The growth-inhibitory effect of curcumin was time and dose dependent, and correlated with its inhibition of or-nithine decarboxylase activity. Curcumin preferentially arrested cells in the G2/S phase of the cell cycle.

Fang et al. reported that rat thioredoxin reductase activity in thioredoxin-dependent disulfide reduction was inhibited by curcumin [50]. By using mass spectrometry and blotting analysis, they showed that this irreversible inhibition by curcumin was caused by alkylation of both residues in the catalytically active site (Cys (496)/Sec (497)) of the enzyme. Kang et al. reported that exposure of human hepatoma cells to curcumin led to a significant decrease of histone acetyla-tion [51]. Curcumin can selectively downregulate transcription of human papillomavirus type 18, which is etiologically associated with development of cancer of the uterine cervix in women, as well as activator protein 1 (AP-1) binding activity in HeLa cells. Most interestingly, curcumin can reverse the expression dynamics of c-fos and fra-1 in this tumorigenic cell line [52].

Curcumin had synergic activity with chemotherapeutic agent vinorelbine in suppressing the growth of human squamous cell lung carcinoma H520 cells [53]. It significantly inhibited the growth of human gastric carcinoma AGS cells in a dose- and time-dependent manner [54]. Using time-lapse video and immunofluorescence labeling methods, Holy et al. demonstrated that curcumin significantly altered microfilament organization and cell motility in PC-3 and LNCaP human prostate cancer cells in vitro [55]. Chemoresistance is a major problem in the treatment of patients with multiple myeloma due to constitutive expression of NF-kB and STAT3. Bharti et al. showed that suppression of NF-kB and STAT3 activation in multiple myeloma cells by ex vivo treatment with curcumin resulted in decreases in adhesion to bone marrow stromal cells, secretion of cytokines, and viability of cells [56].

Helicobacter pylori is a Group 1 carcinogen that is associated with the development of gastric and colon cancers. Curcumin inhibited the growth of all strains of H. pylori in vitro with a minimum inhibitory concentration range of 6.25 to 50 |g/ml [57]. Chen et al. used microarray analysis of gene expression profiles to characterize the anti-invasive mechanisms of curcumin in highly invasive lung ade-nocarcinoma cells (CL1-5) [58]. In these studies, curcumin significantly reduced the invasive capacity of CL1-5 cells in a concentration range far below its levels of cytotoxicity (20 |M), and this anti-invasive effect was concentration dependent. Kim et al. evaluated the antiangiogenic activity of demethoxycurcumin, a structural analog of curcumin, and found that nine angiogenesis-related genes were down-regulated by at least fivefold in response to this agent [59].

Numerous studies have evaluated the cancer-chemopreventive properties of cur-cumin. The anticancer potential of curcumin was examined in vivo in mice using Dalton's lymphoma cells grown as ascites [60]. When curcumin was administered in liposomal formulations at a concentration of 1 mg/animal, all animals survived 30 days and only two of the animals developed tumors and died before 60 days. Similarly, Busquets et al. showed that systemic administration of curcumin for 6 consecutive days to rats bearing the highly cachectic ascites hepatoma resulted in a significant inhibition of tumor growth [61]. Interestingly, curcumin was able to reduce in vitro tumor cell content by 24% at concentrations as low as 0.5 |M without promoting any apoptotic events.

Menon et al. reported curcumin-induced inhibition of B16F10 melanoma lung metastasis in mice [62]. Oral administration of curcumin at concentrations of 200nmol/kg body weight reduced the number of lung tumor nodules by 80%. The life span of the animals treated with curcumin was increased by 143.85% [62]. Curcumin treatment (10|g/ml) significantly inhibited the invasion of B16F10 melanoma cells by inhibition of matrix metalloproteinases (MMP), thereby inhibiting lung metastasis.

Curcumin decreases the proliferative potential and increases the apoptotic potential of both androgen-dependent and androgen-independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGFR [63]. The chemopreventive activity of curcumin was observed when it was administered prior to, during, and after carcinogen treatment as well as when it was given only during the promotion/progression phase of colon carcinogenesis [64]. The chemopreventive effect of curcumin was also examined on the development of adenomas in the intestinal tract of a mouse model of human familial adenomatous polyposis coli [65]. Curcumin at 0.2% and 0.5% of diet reduced adenoma multiplicity by 39% and 40%, respectively.

Odot et al. showed that curcumin was cytotoxic to B16-R melanoma cells resistant to doxorubicin [66]. Treatment with a prophylactic immune preparation of soluble proteins from B16-R cells, in combination with curcumin, resulted in substantial inhibition of growth of B16-R melanoma and a significant increase in the median survival time of the animals.

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