Skip to main content
Top
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Norcantharidin Inhibits cell growth by suppressing the expression and phosphorylation of both EGFR and c-Met in human colon cancer cells

Authors: Peiju Qiu, Siwen Wang, Ming Liu, He Ma, Xuan Zeng, Meng Zhang, Lingling Xu, Yidi Cui, Huixin Xu, Yang Tang, Yanli He, Lijuan Zhang

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Norcantharidin (NCTD) is a Chinese FDA approved, chemically synthesized drug for cancer treatment. The effect of NCTD on signaling proteins of EGFR and c-Met was systematically elucidated in current study.

Methods

Two human colon cancer cell lines, HCT116 and HT29, were used as model systems to investigate the anti-cancer molecular mechanism of NCTD. Cell cycle arrest and early/late apoptosis were analyzed by flow cytometry. The levels of EGFR, phospho-EGFR, c-Met, phospho-c-Met and other related proteins were quantified by western blot analysis.

Results

NCTD induced cell cycle arrest at G2/M phase in both cell lines. The early and late apoptosis was also observed. Further investigation indicated that NCTD suppressed not only the expression of the total EGFR and the phosphorylated EGFR but also the expression of the total c-Met and the phosphorylated c-Met in colon cancer cells. Moreover, EGFR expression could be mostly restored by co-treatment with MG132, a proteasome inhibitor. In addition, NCTD-induced cell death was comparable to that of the anti-cancer drug gefitinib, a tyrosine kinase inhibitor for EGFR, based on the immunoblot analysis of the expressed proteins after the drug treatment.

Conclusions

NCTD might be a useful and inexpensive drug candidate to substitute for gefitinib to serve the treatment needs of cancer patients.
Literature
1.
go back to reference Li CC, Yu FS, Fan MJ, Chen YY, Lien JC, Chou YC, Lu HF, Tang NY, Peng SF, Huang WW, Chung JG. Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo. Environ Toxicol. 2016. doi:10.1002/tox.22273. Li CC, Yu FS, Fan MJ, Chen YY, Lien JC, Chou YC, Lu HF, Tang NY, Peng SF, Huang WW, Chung JG. Anticancer effects of cantharidin in A431 human skin cancer (Epidermoid carcinoma) cells in vitro and in vivo. Environ Toxicol. 2016. doi:10.​1002/​tox.​22273.
2.
go back to reference Le AP, Zhang LL, Liu W, Shi YF. Cantharidin inhibits cell proliferation and induces apoptosis through G2/M phase cell cycle arrest in hepatocellular carcinoma stem cells. Oncol Rep. 2016;35:2970–6.PubMed Le AP, Zhang LL, Liu W, Shi YF. Cantharidin inhibits cell proliferation and induces apoptosis through G2/M phase cell cycle arrest in hepatocellular carcinoma stem cells. Oncol Rep. 2016;35:2970–6.PubMed
3.
go back to reference Shen M, Wu MY, Chen LP, Zhi Q, Gong FR, Chen K, Li DM, Wu Y, Tao M, Li W. Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA. Sci Rep. 2015;5:11836.CrossRefPubMedPubMedCentral Shen M, Wu MY, Chen LP, Zhi Q, Gong FR, Chen K, Li DM, Wu Y, Tao M, Li W. Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA. Sci Rep. 2015;5:11836.CrossRefPubMedPubMedCentral
4.
go back to reference Hsiao YP, Tsai CH, Wu PP, Hsu SC, Liu HC, Huang YP, Yang JH, Chung JG. Cantharidin induces G2/M phase arrest by inhibition of Cdc25c and Cyclin A and triggers apoptosis through reactive oxygen species and the mitochondria-dependent pathways of A375.S2 human melanoma cells. Int J Oncol. 2014;45:2393–402.PubMed Hsiao YP, Tsai CH, Wu PP, Hsu SC, Liu HC, Huang YP, Yang JH, Chung JG. Cantharidin induces G2/M phase arrest by inhibition of Cdc25c and Cyclin A and triggers apoptosis through reactive oxygen species and the mitochondria-dependent pathways of A375.S2 human melanoma cells. Int J Oncol. 2014;45:2393–402.PubMed
5.
go back to reference Cotovio P, Silva C, Guedes Marques M, Ferrer F, Costa F, Carreira A, Campos M. Acute kidney injury by cantharidin poisoning following a silly bet on an ugly beetle. Clin Kidney J. 2013;6:201–3.CrossRefPubMedPubMedCentral Cotovio P, Silva C, Guedes Marques M, Ferrer F, Costa F, Carreira A, Campos M. Acute kidney injury by cantharidin poisoning following a silly bet on an ugly beetle. Clin Kidney J. 2013;6:201–3.CrossRefPubMedPubMedCentral
6.
go back to reference Hsieh CH, Chao KS, Liao HF, Chen YJ. Norcantharidin, derivative of cantharidin, for cancer stem cells. Evid Based Complement Alternat Med. 2013;2013:838651.CrossRefPubMedPubMedCentral Hsieh CH, Chao KS, Liao HF, Chen YJ. Norcantharidin, derivative of cantharidin, for cancer stem cells. Evid Based Complement Alternat Med. 2013;2013:838651.CrossRefPubMedPubMedCentral
7.
go back to reference Chen YN, Chen JC, Yin SC, Wang GS, Tsauer W, Hsu SF, Hsu SL. Effect or mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int J Cancer. 2002;100:158–65.CrossRefPubMed Chen YN, Chen JC, Yin SC, Wang GS, Tsauer W, Hsu SF, Hsu SL. Effect or mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int J Cancer. 2002;100:158–65.CrossRefPubMed
8.
go back to reference Yang PY, Chen MF, Tsai CH, Hu DN, Chang FR, Wu YC. Involvement of caspase and MAPK activities in norcantharidin-induced colorectal cancer cell apoptosis. Toxicol In Vitro. 2010;24:766–75.CrossRefPubMed Yang PY, Chen MF, Tsai CH, Hu DN, Chang FR, Wu YC. Involvement of caspase and MAPK activities in norcantharidin-induced colorectal cancer cell apoptosis. Toxicol In Vitro. 2010;24:766–75.CrossRefPubMed
9.
go back to reference Xie J, Zhang Y, Hu X, Lv R, Xiao D, Jiang L, Bao Q. Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer. Med Oncol. 2015;32:145.CrossRefPubMed Xie J, Zhang Y, Hu X, Lv R, Xiao D, Jiang L, Bao Q. Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer. Med Oncol. 2015;32:145.CrossRefPubMed
10.
go back to reference Yang PY, Chen MF, Kao YH, Hu DN, Chang FR, Wu YC. Norcantharidin induces apoptosis of breast cancer cells: involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription. Toxicol In Vitro. 2011;25:699–707.CrossRefPubMed Yang PY, Chen MF, Kao YH, Hu DN, Chang FR, Wu YC. Norcantharidin induces apoptosis of breast cancer cells: involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription. Toxicol In Vitro. 2011;25:699–707.CrossRefPubMed
11.
go back to reference Chen S, Wan P, Ding W, Li F, He C, Chen P, Li H, Hu Z, Tan W, Li J. Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6. Int J Mol Med. 2013;32:43–50.PubMed Chen S, Wan P, Ding W, Li F, He C, Chen P, Li H, Hu Z, Tan W, Li J. Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6. Int J Mol Med. 2013;32:43–50.PubMed
12.
go back to reference Chen YJ, Shieh CJ, Tsai TH, Kuo CD, Ho LT, Liu TY, Liao HF. Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells. Anticancer Drugs. 2005;16:293–9.CrossRefPubMed Chen YJ, Shieh CJ, Tsai TH, Kuo CD, Ho LT, Liu TY, Liao HF. Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells. Anticancer Drugs. 2005;16:293–9.CrossRefPubMed
13.
go back to reference Chen YJ, Tsai YM, Kuo CD, Ku KL, Shie HS, Liao HF. Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect. Life Sci. 2005;85:642–51.CrossRef Chen YJ, Tsai YM, Kuo CD, Ku KL, Shie HS, Liao HF. Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect. Life Sci. 2005;85:642–51.CrossRef
14.
go back to reference Shen B, He PJ, Shao CL. Norcantharidin induced DU145 cell apoptosis through ROS-mediated mitochondrial dysfunction and energy depletion. PLoS One. 2013;8:e84610.CrossRefPubMedPubMedCentral Shen B, He PJ, Shao CL. Norcantharidin induced DU145 cell apoptosis through ROS-mediated mitochondrial dysfunction and energy depletion. PLoS One. 2013;8:e84610.CrossRefPubMedPubMedCentral
16.
go back to reference Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol. 1998;37:285–9.CrossRefPubMed Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol. 1998;37:285–9.CrossRefPubMed
17.
go back to reference Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol. 2000;21:105–15.CrossRefPubMed Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol. 2000;21:105–15.CrossRefPubMed
18.
go back to reference Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K, Possemato A, Nardone J, Innocenti G, Wetzel R, et al. Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A. 2008;105:692–7.CrossRefPubMedPubMedCentral Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K, Possemato A, Nardone J, Innocenti G, Wetzel R, et al. Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A. 2008;105:692–7.CrossRefPubMedPubMedCentral
19.
go back to reference Liu X, Yao W, Newton RC, Scherle PA. Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Invest Drugs. 2008;17:999–1011.CrossRef Liu X, Yao W, Newton RC, Scherle PA. Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Invest Drugs. 2008;17:999–1011.CrossRef
20.
go back to reference Qiu P, Xu L, Gao L, Zhang M, Wang S, Tong S, Sun Y, Zhang L, Jiang T. Exploring pyrimidine-substituted curcumin analogues: design, synthesis and effects on EGFR signaling. Bioorg Med Chem. 2013;21:5012–20.CrossRefPubMed Qiu P, Xu L, Gao L, Zhang M, Wang S, Tong S, Sun Y, Zhang L, Jiang T. Exploring pyrimidine-substituted curcumin analogues: design, synthesis and effects on EGFR signaling. Bioorg Med Chem. 2013;21:5012–20.CrossRefPubMed
21.
go back to reference Qiu P, Dong P, Guan H, Li S, Ho CT, Pan MH, McClements DJ, Xiao H. Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Mol Nutr Food Res. 2010;54:S244–52.CrossRefPubMed Qiu P, Dong P, Guan H, Li S, Ho CT, Pan MH, McClements DJ, Xiao H. Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Mol Nutr Food Res. 2010;54:S244–52.CrossRefPubMed
22.
go back to reference Hong CY, Huang SC, Lin SK, Lee JJ, Chueh LL, Lee CH, Lin JH, Hsiao M. Norcantharidin-induced post-G (2)/M apoptosis is dependent on wild-type p53 gene. Biochem Biophys Res Commun. 2000;276:278–85.CrossRefPubMed Hong CY, Huang SC, Lin SK, Lee JJ, Chueh LL, Lee CH, Lin JH, Hsiao M. Norcantharidin-induced post-G (2)/M apoptosis is dependent on wild-type p53 gene. Biochem Biophys Res Commun. 2000;276:278–85.CrossRefPubMed
Metadata
Title
Norcantharidin Inhibits cell growth by suppressing the expression and phosphorylation of both EGFR and c-Met in human colon cancer cells
Authors
Peiju Qiu
Siwen Wang
Ming Liu
He Ma
Xuan Zeng
Meng Zhang
Lingling Xu
Yidi Cui
Huixin Xu
Yang Tang
Yanli He
Lijuan Zhang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-3039-x

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine