Mechanisms of curcumin- and EGF-receptor related protein (ERRP)-dependent growth inhibition of colon cancer cells.
Numerous dietary and pharmacological agents have been proposed as alternative strategies for treatment and prevention of colorectal cancer. Curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and treatment of colorectal cancer. EGF-R related protein (ERRP), a recently identified pan-erbB inhibitor, is a potential therapeutic agent for colorectal cancer. Here we examine whether curcumin together with ERRP will cause a greater inhibition of growth of colon cancer cells than either agent alone and the mechanisms of this inhibition. Human colon cancer HCT-116 or HT-29 cells were incubated with increasing doses of curcumin (up to 10 microM) or ERRP (up to 5 microg/ml), or a combination of both for 48 h. We observed that the cell growth inhibition and stimulation of apoptosis in response to the combinatorial treatment was significantly greater than that caused by either agent alone. These changes were associated with decreased activation (tyrosine phosphorylation) of EGFR, ErbB-2, ErbB-3, and/or IGF-1R. Whereas curcumin inhibited constitutive activation of both EGFR and IGF-1R, ERRP decreased activation of EGFR, ErbB-2, and ErbB-3 but had no effect on IGF-1R. Further, the combination therapy caused a greater attenuation of downstream effectors such as NF-kappaB, Akt and BAD activation, and down-regulation of procaspase-3 than that noted with either agent alone. The superior effects of the combinatorial treatment could partly be attributed to inhibition of constitutive activation of EGFRs and IGF-1R signaling pathways.
Reddy
Sudha
S
Veterans Affairs Medical Center, Karmanos Cancer Institute, Department of Internal Medicine, Michigan 48201, USA.
Rishi
Arun K
AK
Xu
Hu
H
Levi
Edi
E
Sarkar
Fazlul H
FH
Majumdar
Adhip P N
AP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000517:prevention & control; D003131:Combined Modality Therapy; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D006023:Glycoproteins; D016328:NF-kappa B; D014443:Tyrosine; C512478:EGFR protein, human; D066246:ErbB Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin