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. 2011 Feb 15;128(4):951-61.
doi: 10.1002/ijc.25410.

Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells

Jyoti Nautiyal  1 , Sanjeev Banerjee, Shailender S Kanwar, Yingjie Yu, Bhaumik B Patel, Fazlul H Sarkar, Adhip P N Majumdar
Affiliations

Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells

Jyoti Nautiyal et al. Int J Cancer. .

Abstract

Colorectal cancer is the third most common form of malignancy, behind prostate and lung cancers. Despite recent advances in medicine, mortality from colorectal cancer remains high, highlighting the need for improved therapies. Numerous studies have demonstrated increased activation of EGFR and its family members (EGFRs), IGF-1R as well as c-Src in colorectal cancer. The current study was undertaken to examine the effectiveness of combination therapy of dasatinib (BMS-354825; Bristol-Myers Squibb), a highly specific inhibitor of Src family kinases (SFK) and a nontoxic dietary agent; curcumin (diferuloylmethane), in colorectal cancer in in vitro and in vivo experimental models. For the latter, we utilized C57BL/6 APC(Min+/-) mice. Initial in vitro studies revealed synergistic interactions between the two agents. Additionally, we have observed that combination treatment causes a much greater inhibition of the following metastatic processes than either agent alone: (i) colony formation, (ii) invasion through extracellular matrix and (iii) tubule formation by endothelial cells. Dasatinib affects the cell adhesion phenotype of colon cancer HCT-116 cells whereas the combination therapy enhances this effect to a greater extent. Preclinical investigation revealed that the combination therapy to be highly effective causing an over 95% regression of intestinal adenomas in Apc(Min+/-) mice, which could be attributed to decreased proliferation and increased apoptosis. In conclusion, our data suggest that combination treatment of dasatinib and curcumin could be a potential therapeutic strategy for colorectal cancer.

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Figures

Figure 1
Figure 1
Effects of dasatinib and/or curcumin on the growth of different colon cancer cells: Growth as determined by MTT assay after 48 hrs incubation with incremental doses of curcumin and/or dasatinib in colon cancer cells (A) HCT-116 (wt), (B) HCT-116 p53 (−/−) (C) HT-29 and (D) SW-620. Dose response curves were generated for the drugs using Calcusyn software.
Figure 2
Figure 2
Effects of dasatinib and/or cucrcumin (A) on levels of phosphorylated forms of EGFR, HER-2, HER-3, IGF-1R and c-Src, (B) on downstream signaling effector proteins and (C) NFκ B activity, in colon cancer HCT-116 (wt) cells following 48h of treatment.
Figure 3
Figure 3
Effects of dasatinib and/or curcumin on morphology as well as anchorage-dependent growth of human colon cancer cells. (A) Photomicrographs depicting changes in the number and size of colonies formed after 8 days of treatment with dasatinib and/or curcumin. One set of treated cells were stained with 0.1% crystal violet stain and photographed at the end of treatment. Other sets of cells were allowed to grow after the removal of drugs, subsequently stained with 0.1% crystal violet stain and photographed after (B) Colony formation after 5 days of recovery (C) Effects of dasatinb and/or curcumin on colony formation and morphological changes after 16 days post-treatment. The experiment was repeated at least three times.
Figure 4
Figure 4
Effects of curcumin and/or dasatinib on (A) extra cellular invasion by colon cancer HCT-116 cells as determined by ECM invasion assay and (B) neo-angiogenesis as determined by tubule formation by HUVECs in the absence (control) or presence of drugs.
Figure 5
Figure 5
(A) The effects of dasatinib and/or curcumin on regression of intestinal tumors in ApcMin+/− mice. (B) Effects of dasatinib and/or curcumin on proliferation and apoptosis in the tissue remnants from adenomas.
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