Dracorhodin perchlorate induces G1/G0 phase arrest and mitochondria-mediated apoptosis in SK-MES-1 human lung squamous carcinoma cells

Zhang,Guangxin; Sun,Mei; Zhang,Yifan; Hua,Peiyan; Li,Xin; Cui,Ranji; Zhang,Xingyi

doi:10.3892/ol.2015.3212

Dracorhodin perchlorate induces G1/G0 phase arrest and mitochondria-mediated apoptosis in SK-MES-1 human lung squamous carcinoma cells

Authors:
- Guangxin Zhang
- Mei Sun
- Yifan Zhang
- Peiyan Hua
- Xin Li
- Ranji Cui
- Xingyi Zhang
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Affiliations: Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China, Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China, Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
Published online on: May 14, 2015 https://doi.org/10.3892/ol.2015.3212
Pages: 240-246
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Dracorhodin perchlorate (DP) has recently been revealed to induce apoptosis in various types of cancer. However, the antitumor potential and molecular mechanisms of DP in human lung cancer have not been previously reported. Therefore, the present study aimed to investigate the effects of DP on cell viability, the cell cycle and apoptosis, using an MTT assay, flow cytometry and western blot studies. DP was identified to induce cellular and DNA morphological changes, and decreased the viability of SK‑MES‑1 human lung squamous carcinoma cells. DP significantly inhibited the growth of SK‑MES‑1 cells by inducing apoptosis and G1/G0 cell cycle arrest in a dose‑dependent manner via activation of p53 (P<0.05). Furthermore, DP promoted the significant upregulation of B cell lymphoma‑2 (Bcl‑2)‑activated X protein and significant downregulation of Bcl‑2 (P<0.05), inducing dissipation of the mitochondrial membrane potential (MMP). In addition, caspase‑3 was activated by DP via the cleavage of its substrate, proteolytic cleavage of poly(ADP‑ribose) polymerase. DP also induced caspase‑independent apoptosis by significantly increasing the protein expression of the apoptosis‑inducing factor (P<0.05), which is localized in mitochondria under the physiological conditions and released into the cytoplasm when MMP is dissipated. Furthermore, the present study demonstrated that DP significantly increased the generation of reactive oxygen species (P<0.05). In conclusion, the current study revealed that DP is able to induce cell cycle arrest and apoptosis in SK‑MES‑1 cells via activation of the mitochondrial pathway, indicating that DP may be a potential leading compound for the development of future lung cancer therapeutic regimes.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Johnson DH: Evolution of cisplatin-based chemotherapy in non-small cell lung cancer: A historical perspective and the eastern cooperative oncology group experience. Chest. 117 (4 Suppl 1):133S–137S. 2000. View Article : Google Scholar : PubMed/NCBI
3	Cragg GM and Newman DJ: Plants as a source of anti-cancer agents. J Ethnopharmacol. 100:72–79. 2005. View Article : Google Scholar : PubMed/NCBI
4	Amin AR, Kucuk O, Khuri FR and Shin DM: Perspectives for cancer prevention with natural compounds. J Clin Oncol. 27:2712–2725. 2009. View Article : Google Scholar : PubMed/NCBI
5	Russo M, Palumbo R, Mupo A, et al: Flavonoid quercetin sensitizes a CD95-resistant cell line to apoptosis by activating protein kinase Calpha. Oncogene. 22:3330–3342. 2003. View Article : Google Scholar : PubMed/NCBI
6	Xia MY, Wang MW, Cui Z, et al: Dracorhodin perchlorate induces apoptosis in HL-60 cells. J Asian Nat Prod Res. 8:335–343. 2006. View Article : Google Scholar : PubMed/NCBI
7	Ferreira CG, Epping M, Kruyt FA and Giaccone G: Apoptosis: Target of cancer therapy. Clin Cancer Res. 8:2024–2034. 2002.PubMed/NCBI
8	Brockmann H and Junge H: Die konstitution des dracorhodins, eines neuen farbstoffes aus dem ‘drachenblut’. Eur J Inorg Chem. 76:751–763. 1943.(In German).
9	Rao GS, Gerhart MA, Lee RT III, et al: Antimicrobial agents from higher plants. Dragon's blood resin. J Nat. Prod. 45:646–648. 1982. View Article : Google Scholar : PubMed/NCBI
10	Gao WF, Zheng H, Wang YS, et al: Synthesis of dracorhodin. Chin J Pharma. 20:247–250. 1989.(In Chinese).
11	Rasul A, Ding C, Li X, et al: Dracorhodin perchlorate inhibits PI3K/Akt and NF-κB activation, up-regulates the expression of p53, and enhances apoptosis. Apoptosis. 17:1104–1119. 2012. View Article : Google Scholar : PubMed/NCBI
12	Xia M, Wang M, Tashiro S, Onodera S, Minami M and Ikejima T: Dracorhodin perchlorate induces A375-S2 cell apoptosis via accumulation of p53 and activation of caspases. Biol Pharm Bull. 28:226–232. 2005. View Article : Google Scholar : PubMed/NCBI
13	Yu JH, Zheng GB, Liu CY, Zhang LY, Gao HM, Zhang YH, Dai CY, Huang L, Meng XY, Zhang WY and Yu XF: Dracorhodin perchlorate induced human breast cancer MCF-7 apoptosis through mitochondrial pathways. Int J Med Sci. 10:1149–1156. 2013. View Article : Google Scholar : PubMed/NCBI
14	Xia M, Wang D, Wang M, Tashiro S, Onodera S, Minami M and Ikejima T: Dracorhodin perchlorate induces apoptosis via activation of caspases and generation of reactive oxygen species. J Pharmacol Sci. 95:273–283. 2004. View Article : Google Scholar : PubMed/NCBI
15	Fridman JS and Lowe SW: Control of apoptosis by p53. Oncogene. 22:9030–9040. 2003. View Article : Google Scholar : PubMed/NCBI
16	Adams JM and Cory S: Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci. 26:61–66. 2001. View Article : Google Scholar : PubMed/NCBI
17	Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G and Vandenabeele P: Toxic proteins released from mitochondria in cell death. Oncogene. 23:2861–2874. 2004. View Article : Google Scholar : PubMed/NCBI
18	Porter AG and Jänicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6:99–104. 1999. View Article : Google Scholar : PubMed/NCBI
19	Araki M, Iida Y, Taketani S, Watanabe K, Ohta T and Saito T: Characterization of photoreceptor cell differentiation in the rat retinal cell culture. Dev Biol. 124:239–247. 1987. View Article : Google Scholar : PubMed/NCBI
20	King KL and Cidlowski JA: Cell cycle regulation and apoptosis. Annu Rev Physiol. 60:601–617. 1998. View Article : Google Scholar : PubMed/NCBI
21	Pan J, She M, Xu ZX, et al: Farnesyltransferase inhibitors induce DNA damage via reactive oxygen species in human cancer cells. Cancer Res. 65:3671–3681. 2005. View Article : Google Scholar : PubMed/NCBI
22	He Y, Ju W, Hao H, Liu Q, Lv L and Zeng F: Dracorhodin perchlorate suppresses proliferation and induces apoptosis in human prostate cancer cell line PC-3. J Huazhong Univ Sci Technolog Med Sci. 31:215–219. 2011. View Article : Google Scholar : PubMed/NCBI
23	Budram-Mahadeo V, Morris PJ and Latchman DS: The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1). Oncogene. 21:6123–6131. 2002. View Article : Google Scholar : PubMed/NCBI
24	Vogelstein B, Lane D and Levine AJ: Surfing the p53 network. Nature. 408:307–310. 2000. View Article : Google Scholar : PubMed/NCBI
25	Das SK, Hashimoto T, Shimizu K, et al: Fucoxanthin induces cell cycle arrest at G₀/G₁ phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. Biochim Biophys Acta. 1726:328–335. 2005. View Article : Google Scholar : PubMed/NCBI
26	Huang DC and Strasser A: BH3-Only proteins-essential initiators of apoptotic cell death. Cell. 103:839–842. 2000. View Article : Google Scholar : PubMed/NCBI
27	Frenzel A, Grespi F, Chmelewskij W and Villunger A: Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis. 14:584–596. 2009. View Article : Google Scholar : PubMed/NCBI
28	Danial NN: BCL-2 family proteins: critical checkpoints of apoptotic cell death. Clin Cancer Res. 13:7254–7263. 2007. View Article : Google Scholar : PubMed/NCBI
29	Schuler M, Bossy-Wetzel E, Goldstein JC, et al: p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release. J Biol Chem. 275:7337–7342. 2000. View Article : Google Scholar : PubMed/NCBI
30	Toshiyuki M and Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 80:293–299. 1995. View Article : Google Scholar : PubMed/NCBI
31	Greiner M, Cárdenas S, Parra C, et al: Adrenalectomy regulates apoptotic-associated genes in rat hippocampus. Endocrine. 15:323–333. 2001. View Article : Google Scholar : PubMed/NCBI
32	Slee EA, Adrain C and Martin SJ: Executioner caspase −3, −6, and −7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem. 276:7320–7326. 2001. View Article : Google Scholar : PubMed/NCBI
33	Norberg E, Orrenius S and Zhivotovsky B: Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). Biochem Biophys Res Commun. 396:95–100. 2010. View Article : Google Scholar : PubMed/NCBI
34	Candé C, Cohen I, Daugas E, et al: Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie. 84:215–22. 2002. View Article : Google Scholar : PubMed/NCBI
35	Kroemer G: The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med. 3:614–620. 1997. View Article : Google Scholar : PubMed/NCBI
36	Johnson TM, Yu ZX, Ferrans VJ, et al: Reactive oxygen species are downstream mediators of p53-dependent apoptosis. Proc Natl Acad Sci USA. 93:11848–11852. 1996. View Article : Google Scholar : PubMed/NCBI
37	Cai J and Jones DP: Mitochondrial redox signaling during apoptosis. J Bioenerg Biomembr. 31:327–334. 1999. View Article : Google Scholar : PubMed/NCBI
38	Simon HU, Haj-Yehia A and Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 5:415–418. 2000. View Article : Google Scholar : PubMed/NCBI
39	Akgul C, Moulding DA and Edwards SW: Molecular control of neutrophil apoptosis. FEBS Lett. 487:318–322. 2001. View Article : Google Scholar : PubMed/NCBI
40	Cimino F, Esposito F, Ammendola R and Russo T: Gene regulation by reactive oxygen species. Curr Top Cell Regul. 35:123–148. 1997.PubMed/NCBI