Crocodile blood extract induces the apoptosis of lung cancer cells through PTEN activity

Ou,Yuqian; Ho,Wing  Shing

doi:10.3892/or.2016.4914

Crocodile blood extract induces the apoptosis of lung cancer cells through PTEN activity

Authors:
- Yuqian Ou
- Wing Shing Ho
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Affiliations: School of Life Sciences, The Chinese University of Hong Kong, NT, Hong Kong, SAR, P.R. China
Published online on: July 5, 2016 https://doi.org/10.3892/or.2016.4914
Pages: 1457-1466

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Abstract

Current treatment strategies for lung cancer cause undesirable side‑effects. Integrated medicine with a curative approach has become a common approach to the treatment strategy. Recent studies suggest that American alligator blood is effective in reducing colorectal cancer cell viability in vitro, but the mechanism remains unclear. In the present study, we aimed to study the anticancer activity of crocodile blood extracts on lung cancer cell line A549 and investigate the possible mechanisms involved. In vitro studies were utilized to investigate the effects on the cancer cells after incubation with the blood extracts. The active fraction that showed more efficacy in inhibiting cell growth was characterized in the supernatant (S2) from whole blood extracts. High performance liquid chromatography (HPLC) analysis revealed that S2 contained more polar moiety from whole blood. S2 induced DNA fragmentation. Cell cycle arrest in the G1/M phase was demonstrated and mitochondrial membrane permeability was disrupted. An increase in the generation of reactive oxygen species (ROS) and increased activities of caspase-3 and caspase-7 were detected. Furthermore, release of cytochrome c, upregulation of expression of Bax, p53, p21, Bid, cleaved forms of the caspase family and PARP along with downregulation of Bcl-2, PCNA, MDM2, caspase‑8, wild types of caspase family proteins and PARP were recorded after treatment with S2 fractions. Moreover, the PI3K/AKT survival pathway was downregulated by S2 fractions in the lung cancer cell line.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Hirsch FR, Spreafico A, Novello S, Wood MD, Simms L and Papotti M: The prognostic and predictive role of histology in advanced non-small cell lung cancer: A literature review. J Thorac Oncol. 3:1468–1481. 2008. View Article : Google Scholar : PubMed/NCBI
3	Crinò L, Weder W, van Meerbeeck J and Felip E; ESMO Guidelines Working Group: Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 21(Suppl 5): v103–v115. 2010. View Article : Google Scholar : PubMed/NCBI
4	Pata S, Yaraksa N, Daduang S, Temsiripong Y, Svasti J, Araki T and Thammasirirak S: Characterization of the novel antibacterial peptide Leucrocin from crocodile (Crocodylus siamensis) white blood cell extracts. Dev Comp Immunol. 35:545–553. 2011. View Article : Google Scholar
5	Phosri S, Mahakunakorn P, Lueangsakulthai J, Jangpromma N, Swatsitang P, Daduang S, Dhiravisit A and Thammasirirak S: An investigation of antioxidant and anti-inflammatory activities from blood components of crocodile (Crocodylus siamensis). Protein J. 33:484–492. 2014. View Article : Google Scholar : PubMed/NCBI
6	Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH and Boyd MR: Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 48:589–601. 1988.PubMed/NCBI
7	Kressel M and Groscurth P: Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA. Cell Tissue Res. 278:549–556. 1994. View Article : Google Scholar : PubMed/NCBI
8	Abraham RT: Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15:2177–2196. 2001. View Article : Google Scholar : PubMed/NCBI
9	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
10	Waga S, Hannon GJ, Beach D and Stillman B: The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 369:574–578. 1994. View Article : Google Scholar : PubMed/NCBI
11	Bellamy CO, Clarke AR, Wyllie AH and Harrison DJ: p53 Deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. FASEB J. 11:591–599. 1997.PubMed/NCBI
12	Green DR: Apoptotic pathways: Ten minutes to dead. Cell. 121:671–674. 2005. View Article : Google Scholar : PubMed/NCBI
13	Cui H, Kong Y and Zhang H: Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct. 2012:6463542012. View Article : Google Scholar
14	Aon MA, Cortassa S and O'Rourke B: Mitochondrial oscillations in physiology and pathophysiology. Adv Exp Med Biol. 641:98–117. 2008. View Article : Google Scholar : PubMed/NCBI
15	Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
16	Haga N, Fujita N and Tsuruo T: Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis. Oncogene. 22:5579–5585. 2003. View Article : Google Scholar : PubMed/NCBI
17	Denecker G, Vercammen D, Declercq W and Vandenabeele P: Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci. 58:356–370. 2001. View Article : Google Scholar : PubMed/NCBI
18	Fuertes MA, Castilla J, Alonso C and Pérez JM: Cisplatin biochemical mechanism of action: From cytotoxicity to induction of cell death through interconnections between apoptotic and necrotic pathways. Curr Med Chem. 10:257–266. 2003. View Article : Google Scholar : PubMed/NCBI
19	Yang W, Zhang Y, Li Y, Wu Z and Zhu D: Myostatin induces cyclin D1 degradation to cause cell cycle arrest through a phosphatidylinositol 3-kinase/AKT/GSK-3 β pathway and is antagonized by insulin-like growth factor 1. J Biol Chem. 282:3799–3808. 2007. View Article : Google Scholar
20	Vousden KH and Ryan KM: p53 and metabolism. Nat Rev Cancer. 9:691–700. 2009. View Article : Google Scholar : PubMed/NCBI
21	Finlan LE and Hupp TR: The life cycle of p53: A key target in drug development. Apoptosis Pathways as Targets for Novel Therapies in Cancer and Other Diseases. Los M and Gibson SB: Springer; New York, NY, USA: pp. 157–172. 2005, View Article : Google Scholar
22	Yan X, Fraser M, Qiu Q and Tsang BK: Overexpression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner. Gynecol Oncol. 102:348–355. 2006. View Article : Google Scholar : PubMed/NCBI
23	Moghaddam SJ, Li H, Cho SN, Dishop MK, Wistuba II, Ji L, Kurie JM, Dickey BF and Demayo FJ: Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model. Am J Respir Cell Mol Biol. 40:443–453. 2009. View Article : Google Scholar