Crotoxin suppresses the tumorigenic properties and enhances the antitumor activity of Iressa® (gefinitib) in human lung adenocarcinoma SPCA‑1 cells

Wang,Junhua; Qin,Xiuguang; Zhang,Zhiqiang; Chen,Meiling; Wang,Ying; Gao,Baoqin

doi:10.3892/mmr.2014.2620

December-2014 Volume 10 Issue 6

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

December-2014 Volume 10 Issue 6

Full Size Image

Article

Crotoxin suppresses the tumorigenic properties and enhances the antitumor activity of Iressa® (gefinitib) in human lung adenocarcinoma SPCA‑1 cells

Authors:
- Junhua Wang
- Xiuguang Qin
- Zhiqiang Zhang
- Meiling Chen
- Ying Wang
- Baoqin Gao
View Affiliations / Copyright

Affiliations: Department of Cardiothoracic Surgery, The First Hospital Affiliated to the Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China, Department of Thoracic Surgery, The First Hospital Affiliated to the Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China, Department of Respiratory Medicine, The First Hospital Affiliated to the Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China, Department of Oncology, The First Hospital Affiliated to the Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China, Department of Operating Room, The First Hospital Affiliated to the Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China
Pages: 3009-3014
|
Published online on: October 9, 2014

https://doi.org/10.3892/mmr.2014.2620
Expand metrics +

Abstract

Crotoxin (CrTX) is a neurotoxin isolated from the venom of the South American rattlesnake. Previous studies demonstrated that CrTX was able to inhibit the activity of the growth factor receptor tyrosine kinase and that CrTX possesses potent antitumor activity when combined with Iressa, an epidermal growth factor receptor inhibitor. The aim of the present study was to determine the antitumor effect of CrTX and the combination of CrTX with Iressa in lung adenocarcinoma SPCA‑1 cells. The results demonstrated that CrTX inhibited the cellular growth of SPCA‑1 cells via G1 arrest and induction of apoptosis. In addition, the c‑Jun N‑terminal kinase pathway was important in CrTX‑induced apoptosis in SPCA‑1 cells. Notably, CrTX was able to significantly enhance the cytotoxic effects of Iressa in SPCA‑1 cells. The in vivo antitumor assay demonstrated that treatment with either CrTX or Iressa significantly inhibited tumor growth, while the combination of CrTX and Iressa demonstrated the most significant antitumor activity, which was reflected by tumor weight and angiogenesis, presented as microvascular density. Therefore, the present study suggested that CrTX is a potential anti‑lung cancer agent and sensitizer of Iressa.

View Figures

View References

1	Dempke WC, Suto T and Reck M: Targeted therapies for non-small cell lung cancer. Lung Cancer. 67:257–274. 2010. View Article : Google Scholar : PubMed/NCBI
2	Centers for Disease Control and Prevention (CDC). Lung Cancer Fact Sheet. CDC; Atlanta, GA, USA: pp. 156–157. 2009
3	Rübsamen K, Breithaupt H and Habermann E: Biochemistry and pharmacology of the crotoxin complex. I Subfractionation and recombination of the crotoxin complex. Naunyn Schmiedebergs Arch Pharmakol. 270:274–288. 1971.PubMed/NCBI
4	Délot E and Bon C: Model for the interaction of crotoxin, a phospholipase A2 neurotoxin, with presynaptic membranes. Biochemistry. 32:10708–10713. 1993.PubMed/NCBI
5	Faure G, Harvey AL, Thomson E, Saliou B, Radvanyi F and Bon C: Comparison of crotoxin isoforms reveals that stability of the complex plays a major role in its pharmacological action. Eur J Biochem. 214:491–496. 1993. View Article : Google Scholar : PubMed/NCBI
6	Aird SD, Kaiser II, Lewis RV and Kruggel WG: A complete amino acid sequence for the basic subunit of crotoxin. Arch Biochem Biophys. 249:296–300. 1986. View Article : Google Scholar : PubMed/NCBI
7	Corin RE, Viskatis LJ, Vidal JC and Etcheverry MA: Cytotoxicity of crotoxin on murine erythroleukemia cells in vitro. Invest New Drugs. 11:11–15. 1993. View Article : Google Scholar : PubMed/NCBI
8	Rudd CJ, Viskatis LJ, Vidal JC and Etcheverry MA: In vitro comparison of cytotoxic effects of crotoxin against three human tumors and a normal human epidermal keratinocyte cell line. Invest New Drugs. 12:183–184. 1994. View Article : Google Scholar : PubMed/NCBI
9	Newman RA, Vidal JC, Viskatis LJ, Johnson J and Etcheverry MA: VRCTC-310 - a novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity. Invest New Drugs. 11:151–159. 1993. View Article : Google Scholar : PubMed/NCBI
10	Yan CH, Yang YP, Qin ZH, Gu ZL, Reid P and Liang ZQ: Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells. Acta Pharmacol Sin. 28:540–548. 2007. View Article : Google Scholar : PubMed/NCBI
11	Zhang M, Zhang X, Bai CX, Chen J and Wei MQ: Inhibition of epidermal growth factor receptor expression by RNA interference in A549 cells. Acta Pharmacol Sin. 25:61–67. 2004.PubMed/NCBI
12	Wang JH, Xie Y, Wu JC, et al: Crotoxin enhances the antitumor activity of gefinitib (Iressa) in SK-MES-1 human lung squamous carcinoma cells. Oncol Rep. 27:1341–1347. 2012.PubMed/NCBI
13	Wang Q, Tan YX, Ren YB, et al: Zinc finger protein ZBTB20 expression is increased in hepatocellular carcinoma and associated with poor prognosis. BMC Cancer. 11:2712011. View Article : Google Scholar : PubMed/NCBI
14	Weidner N, Semple JP, Welch WR and Folkman J: Tumor angiogenesis and metastasis - correlation in invasive breast carcinoma. N Engl J Med. 324:1–8. 1991. View Article : Google Scholar : PubMed/NCBI
15	Donato NJ, Martin CA, Perez M, Newman RA, Vidal JC and Etcheverry M: Regulation of epidermal growth factor receptor activity by crotoxin, a snake venom phospholipase A2 toxin. A novel growth inhibitory mechanism. Biochem Pharmacol. 51:1535–1543. 1996. View Article : Google Scholar : PubMed/NCBI
16	Condrea E: Membrane-active polypeptides from snake venom: cardiotoxins and haemocytotoxins. Experientia. 30:121–129. 1974. View Article : Google Scholar : PubMed/NCBI
17	Yan CH, Liang ZQ, Gu ZL, Yang YP, Reid P and Qin ZH: Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. Toxicon. 47:521–530. 2006. View Article : Google Scholar : PubMed/NCBI
18	Cura JE, Blanzaco DP, Brisson C, et al: Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-624244) in patients with advanced cancer. Clin Cancer Res. 8:1033–1041. 2002.PubMed/NCBI
19	Stinchcombe TE and Bogart JA: Novel approaches of chemoradiotherapy in unresectable stage IIIA and stage IIIB non-small cell lung cancer. Oncologist. 17:682–693. 2012. View Article : Google Scholar : PubMed/NCBI
20	Li Y and Song L: Research progress on resistance mechanisms of epidermal growth factor receptortyrosine kinase inhibitors in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 15:106–111. 2012.(In Chinese).
21	Brand TM, Iida M, Li C and Wheeler DL: The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discov Med. 12:419–432. 2011.PubMed/NCBI