Norcantharidin suppresses cell growth and migration with enhanced anticancer activity of gefitinib and cisplatin in human non-small cell lung cancer cells

Lee,Ya-Chun; Lee,Liang-Ming; Yang,Chih-Hsin; Lin,Anya  Maan-Yuh; Huang,Yi-Chia; Hsu,Chia-Chi; Chen,Meng-Shian; Chi,Chin-Wen; Yin,Pen-Hui; Kuo,Cheng-Deng; Liao,Jyh-Fei; Lee,Hsin-Chen

doi:10.3892/or.2012.2118

Norcantharidin suppresses cell growth and migration with enhanced anticancer activity of gefitinib and cisplatin in human non-small cell lung cancer cells

Authors:
- Ya-Chun Lee
- Liang-Ming Lee
- Chih-Hsin Yang
- Anya Maan-Yuh Lin
- Yi-Chia Huang
- Chia-Chi Hsu
- Meng-Shian Chen
- Chin-Wen Chi
- Pen-Hui Yin
- Cheng-Deng Kuo
- Jyh-Fei Liao
- Hsin-Chen Lee
View Affiliations

Affiliations: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C., Department of Urology, Taipei Medical University-Affiliated Taipei Municipal Wan-Fang Hospital, Taipei, Taiwan, R.O.C., Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, R.O.C., Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
Published online on: October 31, 2012 https://doi.org/10.3892/or.2012.2118
Pages: 237-243

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Norcantharidin is the demethylated analog of cantharidin isolated from blister beetles (Mylabris phalerata Pall.). In this study, we evaluated whether norcantharidin exhibits anticancer effects against the human non-small cell lung cancer cell lines A549 (epidermal growth factor receptor (EGFR) mutation-negative) and PC9 (EGFR mutation-positive). Our results revealed that norcantharidin dose-dependently retards cell growth, arrests cell cycle at G2/M phase, reduces cell migration, and even induces apoptosis at the concentration of 100 µM. Moreover, we found that norcantharidin enhances the anticancer effects of gefitinib and cisplatin. Norcantharidin exhibited similar potency of anticancer effects against the two cell lines with different EGFR mutation status and did not affect EGF-induced EGFR phosphorylation, suggesting that the EGFR signaling may not be the target of norcantharidin. In conclusion, our results suggest that norcantharidin exhibits anticancer effects against non-small cell lung cancer cells in vitro and support its potential as a chemotherapeutic agent for treating non-small cell lung cancer.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: 2011 Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Ramalingam S and Belani C: Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist. 13:5–13. 2008. View Article : Google Scholar : PubMed/NCBI
3	Sharma SV, Bell DW, Settleman J and Haber DA: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 7:169–181. 2007. View Article : Google Scholar : PubMed/NCBI
4	Mendelsohn J: Blockade of receptors for growth factors: an anticancer therapy - the fourth annual Joseph H. Burchenal American Association of Cancer Research Clinical Research Award Lecture. Clin Cancer Res. 6:747–753. 2000.
5	Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD Jr, Morse D, Abraham S, Rahman A, Liang C, Lostritto R, Baird A and Pazdur R: United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res. 10:1212–1218. 2004. View Article : Google Scholar : PubMed/NCBI
6	Wu JY, Shih JY, Chen KY, Yang CH, Yu CJ and Yang PC: Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations. Medicine. 90:159–167. 2011. View Article : Google Scholar : PubMed/NCBI
7	Lacouture ME: Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 6:803–812. 2006. View Article : Google Scholar : PubMed/NCBI
8	Jiang H: Overview of gefitinib in non-small cell lung cancer: an Asian perspective. Jpn J Clin Oncol. 39:137–150. 2009. View Article : Google Scholar : PubMed/NCBI
9	Wang GS: Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol. 26:147–162. 1989. View Article : Google Scholar : PubMed/NCBI
10	Chen YN, Chen JC, Yin SC, Wang GS, Tsauer W, Hsu SF and Hsu SL: Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int J Cancer. 100:158–165. 2002. View Article : Google Scholar : PubMed/NCBI
11	Hill TA, Stewart SG, Ackland SP, Gilbert J, Sauer B, Sakoff JA and McCluskey A: Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation. Bioorg Med Chem. 15:6126–6134. 2007. View Article : Google Scholar : PubMed/NCBI
12	Fan YZ, Fu JY, Zhao ZM and Chen CQ: Inhibitory effect of norcantharidin on the growth of human gallbladder carcinoma GBC-SD cells in vitro. Hepatobiliary Pancreat Dis Int. 6:72–80. 2007.PubMed/NCBI
13	Peng F, Wei YQ, Tian L, Yang L, Zhao X, Lu Y, Mao YQ, Kan B, Lei S, Wang GS, Jiang Y, Wang QR, Luo F, Zou LQ and Liu JY: Induction of apoptosis by norcantharidin in human colorectal carcinoma cell lines: involvement of the CD95 receptor/ligand. J Cancer Res Clin Oncol. 128:223–230. 2002. View Article : Google Scholar : PubMed/NCBI
14	Liao HF, Su SL, Chen YJ, Chou CH and Kuo CD: Norcantharidin preferentially induces apoptosis in human leukemic Jurkat cells without affecting viability of normal blood mononuclear cells. Food Chem Toxicol. 45:1678–1687. 2007. View Article : Google Scholar
15	Chen YJ, Shieh CJ, Tsai TH, Kuo CD, Ho LT, Liu TY and Liao HF: Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells. Anticancer Drugs. 16:293–299. 2005. View Article : Google Scholar
16	Chen YJ, Tsai YM, Kuo CD, Ku KL, Shie HS and Liao HF: Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect. Life Sci. 85:642–651. 2009. View Article : Google Scholar : PubMed/NCBI
17	Yang EB, Tang WY, Zhang K, Cheng LY and Mack PO: Norcantharidin inhibits growth of human HepG2 cell-transplanted tumor in nude mice and prolongs host survival. Cancer Lett. 117:93–98. 1997. View Article : Google Scholar : PubMed/NCBI
18	Fan YZ, Zhao ZM, Fu JY, Chen CQ and Sun W: Norcantharidin inhibits growth of human gallbladder carcinoma xenografted tumors in nude mice by inducing apoptosis and blocking the cell cycle in vivo. Hepatobiliary Pancreat Dis Int. 9:414–422. 2010.PubMed/NCBI
19	Liu XH, Blazsek I, Comisso M, Legras S, Marion S, Quittet P, Anjo A, Wang GS and Misset JL: Effects of norcantharidin, a protein phosphatase type-2A inhibitor, on the growth of normal and malignant haemopoietic cells. Eur J Cancer. 31A:953–963. 1995.PubMed/NCBI
20	McCluskey A, Ackland SP, Gardiner E, Walkom CC and Sakoff JA: The inhibition of protein phosphatases 1 and 2A: a new target for rational anti-cancer drug design? Anticancer Drug Des. 16:291–303. 2001.PubMed/NCBI
21	Hill TA, Stewart SG, Sauer B, Gilbert J, Ackland SP, Sakoff JA and McCluskey A: Heterocyclic substituted cantharidin and norcantharidin analogues-synthesis, protein phosphatase (1 and 2A) inhibition, and anti-cancer activity. Bioorg Med Chem Lett. 17:3392–3397. 2007. View Article : Google Scholar
22	Wu CW, Ping YH, Yen JC, Chang CY, Wang SF, Yeh CL, Chi CW and Lee HC: Enhanced oxidative stress and aberrant mitochondrial biogenesis in human neuroblastoma SH-SY5Y cells during methamphetamine induced apoptosis. Toxicol Applied Pharmacol. 220:243–251. 2007. View Article : Google Scholar
23	Luan J, Duan H, Liu Q, Yagasaki K and Zhang G: Inhibitory effects of norcantharidin against human lung cancer cell growth and migration. Cytotechnology. 62:349–355. 2010. View Article : Google Scholar : PubMed/NCBI
24	Hong CY, Huang SC, Lin SK, Lee JJ, Chueh LL, Lee CH, Lin JH and Hsiao M: Norcantharidin-induced post-G(2)/M apoptosis is dependent on wild-type p53 gene. Biochem Biophys Res Commun. 276:278–285. 2000. View Article : Google Scholar : PubMed/NCBI
25	Liao HF, Chen YJ, Chou CH, Wang FW and Kuo CD: Norcantharidin induces cell cycle arrest and inhibits progression of human leukemic Jurkat T cells through mitogen-activated protein kinase-mediated regulation of interleukin-2 production. Toxicol In Vitro. 25:206–212. 2011. View Article : Google Scholar
26	Yang PY, Chen MF, Kao YH, Hu DN, Chang FR and 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. 25:699–707. 2011. View Article : Google Scholar : PubMed/NCBI
27	Millward TA, Zolnierowicz S and Hemmings BA: Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 24:186–191. 1999. View Article : Google Scholar : PubMed/NCBI