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

• Published in: International journal of cancer Vol. 128; no. 4; pp. 951 - 961
• Main Authors: Nautiyal, Jyoti, Banerjee, Sanjeev, Kanwar, Shailender S., Yu, Yingjie, Patel, Bhaumik B, Sarkar, Fazlul H., Majumdar, Adhip P.N.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.02.2011; Wiley-Blackwell
• Subjects: Adenoma - drug therapy; Adenoma - metabolism; Adenoma - pathology; Adenomatous Polyposis Coli Protein - physiology; Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Cell Adhesion; cell invasion and angiogenesis; Cell Movement; Cell Proliferation - drug effects; cell signaling; Cell Transformation, Neoplastic - drug effects; Cells, Cultured; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; combination therapy; Curcumin - pharmacology; Dasatinib; Drug Synergism; Electrophoretic Mobility Shift Assay; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunoenzyme Techniques; Intestinal Neoplasms - drug therapy; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Medical sciences; Mice; Mice, Knockout; Neoplasm Invasiveness; Neovascularization, Pathologic; NF-kappa B - genetics; NF-kappa B - metabolism; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - metabolism; Pyrimidines - pharmacology; Receptor, Epidermal Growth Factor - metabolism; Receptor, IGF Type 1 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; src-Family Kinases; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; synergistic interactions; Thiazoles - pharmacology; tumor regression; Tumors; Umbilical Veins - cytology; Umbilical Veins - drug effects; Umbilical Veins - metabolism; Antineoplastic agent; Growth; Metastasis; Cell transformation; Carcinogenesis; synergistic interactions; Angiogenesis; Signal transduction; Polyphenol; cell invasion and angiogenesis; Colon cancer; Cancerology; Intestinal disease; combination therapy; Curcumin; Drug interaction; tumor regression; Neovascularization; Tumor cell; Dasatinib; Tyrosine kinase inhibitor; Regression; Malignant tumor; Invasion; Colonic disease; cell signaling; Phenols; Digestive diseases; Combined treatment; Multikinase inhibitor; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25410

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 APCMin+/− 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 ApcMin+/− 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.