Synergistic Inhibitory Effects of Cetuximab and Cisplatin on Human Colon Cancer Cell Growth via Inhibition of the ERK-Dependent EGF Receptor Signaling Pathway.
The purpose of this study was to evaluate the anticancer efficacy of cetuximab combined with cisplatin (combination treatment) on colon cancer growth, as well as its underlying action mechanism. Combination treatment synergistically potentiated the effect of cetuximab on cell growth inhibition and apoptosis induction in HCT116 and SW480 cells. Combination treatment further suppressed the expression of the activated form of epidermal growth factor receptor (EGFR) and MAP kinase (p-ERK and p-p38) and also significantly inhibited the activity of activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). Additionally, the expression of cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA was significantly reduced by the combination treatment as compared to the expression seen for treatment with cetuximab or cisplatin alone. We found that the synergistic inhibitory effects of cetuximab and cisplatin on AP-1 and NF-κB activation, as well as on cell viability, were reversed by pretreatment with an ERK inhibitor. Results demonstrate that combined treatment with cetuximab and cisplatin exerts synergistic anticancer effects on colon cancer cells and also suggest that the ERK pathway plays a critical role in these effects via the suppression of the EGFR signaling pathway, along with the inhibition of COX-2, IL-8, and AP-1 and NF-κB.
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Dong Ju
DJ
Son
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Ji Eun
JE
Hong
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Jung Ok
JO
Ban
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Ju Ho
JH
Park
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Hye Lim
HL
Lee
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Sun Mi
SM
Gu
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Jae Yeon
JY
Hwang
Korea Health Industry Development Institute (KHIDI), Cheongju, Chungbuk 363-951, Republic of Korea.
Myung Hee
MH
Jung
Ministry of Food and Drug Safety (MFDS), Cheongju, Chungbuk 361-709, Republic of Korea.
Dong Won
DW
Lee
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Sang-Bae
SB
Han
College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Jin Tae
JT
Hong
D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology*; D002945:Cisplatin / Q000819:agonists / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*
C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin