Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis.
Nafamostat mesilate is an anti-inflammatory drug that is usually used to treat pancreatitis. Recent studies show that it can suppress pancreatic cancer via inhibition of the nuclear factor κB (NF-κB) pathway. However, whether it has anti-tumor activity in some other cancer, including colorectal cancer (CRC), has not been investigated and remained unclear. Here, our study showed that nafamostat mesilate abrogated the constitutive NF-κB activation in CRC cells, which is mediated through inhibition of phosphorylation of IκBα and nuclear translocation of p65. Also, we found that nafamostat mesilate inhibited phosphorylation of Erk in CRC cells. Consistently, our study demonstrated that nafamostat mesilate inhibited the CRC cell proliferation, invasion and migration and induced mitochondria-dependent apoptosis. Furthermore, nafamostat mesilate could reverse oxaliplatin induced NF-κB and Erk activation in CRC cells, and enhance the sensitivity of CRC cells to oxaliplatin. Nafamostat mesilate combined with oxaliplatin repressed subcutaneous tumor growth and hepatic metastasis in vivo. Overall, our data suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Yun-Xin
YX
Lu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Huai-Qiang
HQ
Ju
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Feng
F
Wang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Le-Zong
LZ
Chen
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Qi-Nian
QN
Wu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Hui
H
Sheng
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Hai-Yu
HY
Mo
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
Zhi-Zhong
ZZ
Pan
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Dan
D
Xie
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Tie-Bang
TB
Kang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
Gong
G
Chen
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Jing-Ping
JP
Yun
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Zhao-Lei
ZL
Zeng
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: xurh@sysucc.org.cn.
Rui-Hua
RH
Xu
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001550:Benzamidines; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D001550:Benzamidines; D006146:Guanidines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009944:Organoplatinum Compounds; C498143:RELA protein, human; D051996:Transcription Factor RelA; D000077150:Oxaliplatin; D000072000:NF-KappaB Inhibitor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; C032855:nafamostat
Chemoresistance; Colorectal cancer; Nafamostat mesilate; Nuclear factor kappa B; Oxaliplatin