Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells.
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.
Nautiyal
Jyoti
J
Veterans Affairs Medical Center, Detroit, MI 48201, USA.
Banerjee
Sanjeev
S
Kanwar
Shailender S
SS
Yu
Yingjie
Y
Patel
Bhaumik B
BB
Sarkar
Fazlul H
FH
Majumdar
Adhip P N
AP
D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003474:Curcumin / Q000494:pharmacology*; D000069439:Dasatinib; D004357:Drug Synergism; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases
D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D013844:Thiazoles; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D003474:Curcumin; D000069439:Dasatinib
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