Pingyangmycin stimulates apoptosis in human hemangioma‑derived endothelial cells through activation of the p53 pathway

Tu,Jun‑Bo; Li,Quan‑Yan; Jiang,Fei; Hu,Xiao‑Yi; Ma,Rui‑Zhao; Dong,Qiang; Zhang,Hao; Pattar,Parukjan; Li,Shi‑Xian

doi:10.3892/mmr.2014.2174

Pingyangmycin stimulates apoptosis in human hemangioma‑derived endothelial cells through activation of the p53 pathway

Authors:
- Jun‑Bo Tu
- Quan‑Yan Li
- Fei Jiang
- Xiao‑Yi Hu
- Rui‑Zhao Ma
- Qiang Dong
- Hao Zhang
- Parukjan Pattar
- Shi‑Xian Li
View Affiliations

Affiliations: Department of Oral and Maxillofacial Surgery, Stomatological Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Oral and Maxillofacial Surgery, Weihai Stomatological Hospital, Weihai, Shandong 264200, P.R. China
Published online on: April 24, 2014 https://doi.org/10.3892/mmr.2014.2174
Pages: 301-305

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

Pingyangmycin (also known as Bleomycin A5) is produced by Streptomyces verticillus var. pingyangensis n.sp., and has anti‑tumor activities against a variety of tumor cells. The aim of the present study was to determine the molecular mechanism(s) underlying the therapeutic effects of pingyangmycin against infantile hemangiomas. Human hemangioma‑derived endothelial cells (HemECs) were treated with pingyangmycin at varying concentrations (100, 200 or 300 µg/ml), and the morphological changes and apoptosis levels were assessed. The gene expression changes were determined by cDNA microarray technology. Transmission electron microscopy examination revealed that the pingyangmycin‑treated HemECs exhibited typical apoptotic characteristics, including chromatin condensation and the formation of apoptotic bodies. Annexin‑V staining demonstrated that pingyangmycin caused a significant and dose‑dependent induction of apoptosis in the HemECs. In the pingyangmycin‑treated HemECs, 4,752 genes demonstrated at least 2‑fold expression changes at the mRNA level. Quantitative polymerase chain reaction confirmed that pingyangmycin significantly upregulated the expression of p53, p53‑induced protein with death domain, Bax, p53 upregulated modulator of apoptosis and p53 inducible gene 3, and downregulated the expression of murine double minute 2. The data demonstrated that the pro‑apoptotic activity of pingyangmycin against infantile hemangiomas involves p53 pathway activation.

View Figures

View References

1	Mendiratta V and Jabeen M: Infantile hemangioma: an update. Indian J Dermatol Venereol Leprol. 76:469–475. 2010. View Article : Google Scholar : PubMed/NCBI
2	Kwon EK, Seefeldt M and Drolet BA: Infantile hemangiomas: an update. Am J Clin Dermatol. 14:111–123. 2013. View Article : Google Scholar : PubMed/NCBI
3	Eivazi B and Werner JA: Management of vascular malformations and hemangiomas of the head and neck - an update. Curr Opin Otolaryngol Head Neck Surg. 21:157–163. 2013. View Article : Google Scholar : PubMed/NCBI
4	Itinteang T, Withers AH, Leadbitter P, et al: Pharmacologic therapies for infantile hemangioma: is there a rational basis? Plast Reconstr Surg. 128:499–507. 2011. View Article : Google Scholar : PubMed/NCBI
5	Bischoff J: Monoclonal expansion of endothelial cells in hemangioma: an intrinsic defect with extrinsic consequences? Trends Cardiovasc Med. 12:220–224. 2002. View Article : Google Scholar : PubMed/NCBI
6	Peng Q, Liu W, Zhou F, et al: An experimental study on the therapy of infantile hemangioma with recombinant interferon γ. Pediatr Surg. 46:496–501. 2011.PubMed/NCBI
7	Storch CH and Hoeger PH: Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 163:269–274. 2010. View Article : Google Scholar : PubMed/NCBI
8	Ouyang L, Shi Z, Zhao S, et al: Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45:487–498. 2012. View Article : Google Scholar : PubMed/NCBI
9	Haupt S, Berger M, Goldberg Z and Haupt Y: Apoptosis - the p53 network. J Cell Sci. 116:4077–4085. 2003. View Article : Google Scholar : PubMed/NCBI
10	Dai F, Chen Y, Song Y, et al: A natural small molecule harmine inhibits angiogenesis and suppresses tumour growth through activation of p53 in endothelial cells. PLoS One. 7:e521622012. View Article : Google Scholar : PubMed/NCBI
11	Ji Y, Li K, Xiao X, et al: Effects of propranolol on the proliferation and apoptosis of hemangioma-derived endothelial cells. J Pediatr Surg. 47:2216–2223. 2012. View Article : Google Scholar : PubMed/NCBI
12	Chen P, Liu B and Hu M: The effect of hydroxycamptothecin and pingyangmycin on human squamous cell carcinoma of the tongue. Oncol Lett. 5:947–952. 2013.PubMed/NCBI
13	Gong JH, Liu XJ, Li Y and Zhen YS: Pingyangmycin downregulates the expression of EGFR and enhances the effects of cetuximab on esophageal cancer cells and the xenograft in athymic mice. Cancer Chemother Pharmacol. 69:1323–1332. 2012. View Article : Google Scholar : PubMed/NCBI
14	Hou J, Wang M, Tang H, et al: Pingyangmycin sclerotherapy for infantile hemangiomas in oral and maxillofacial regions: an evaluation of 66 consecutive patients. Int J Oral Maxillofac Surg. 40:1246–1251. 2011. View Article : Google Scholar : PubMed/NCBI
15	Luo QF and Zhao FY: The effects of Bleomycin A5 on infantile maxillofacial haemangioma. Head Face Med. 7:112011. View Article : Google Scholar : PubMed/NCBI
16	Tu JB, Dong Q, Hu XY, et al: Proteomic analysis of mitochondria from infantile hemangioma endothelial cells treated with sodium morrhuate and its liposomal formulation. J Biochem Mol Toxicol. 26:374–380. 2012. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001.
18	Guan JY, He XF, Chen Y, et al: Percutaneous intratumoral injection with pingyangmycin lipiodol emulsion for the treatment of recurrent sacrococcygeal chordomas. J Vasc Interv Radiol. 22:1216–1220. 2011. View Article : Google Scholar : PubMed/NCBI
19	Ho YC, Tai KW and Chang YC: Synergistic effects of verapamil on pingyangmycin-induced cytotoxicity and apoptosis in KB cells. Oral Dis. 13:40–44. 2007. View Article : Google Scholar : PubMed/NCBI
20	Sgonc R, Fuerhapter C, Boeck G, et al: Induction of apoptosis in human dermal microvascular endothelial cells and infantile hemangiomas by interferon-alpha. Int Arch Allergy Immunol. 117:209–214. 1998.PubMed/NCBI
21	Sethi G, Shanmugam MK, Ramachandran L, et al: Multifaceted link between cancer and inflammation. Biosci Rep. 32:1–15. 2012. View Article : Google Scholar : PubMed/NCBI
22	Lindgren T, Stigbrand T, Riklund K, et al: Gene expression profiling in MOLT-4 cells during gamma-radiation-induced apoptosis. Tumour Biol. 33:689–700. 2012. View Article : Google Scholar : PubMed/NCBI
23	Di J, Zhang Y and Zheng J: Reactivation of p53 by inhibiting Mdm2 E3 ligase: a novel antitumor approach. Curr Cancer Drug Targets. 11:987–994. 2011. View Article : Google Scholar : PubMed/NCBI
24	Bradley G, Tremblay S, Irish J, et al: The expression of p53-induced protein with death domain (Pidd) and apoptosis in oral squamous cell carcinoma. Br J Cancer. 96:1425–1432. 2007.PubMed/NCBI
25	Nakano K and Vousden KH: PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 7:683–694. 2001. View Article : Google Scholar : PubMed/NCBI
26	Nicholls CD, Shields MA, Lee PW, et al: UV-dependent alternative splicing uncouples p53 activity and PIG3 gene function through rapid proteolytic degradation. J Biol Chem. 279:24171–24178. 2004. View Article : Google Scholar : PubMed/NCBI
27	Lee JH, Kang Y, Khare V, et al: The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage. Oncogene. 29:1431–1450. 2010. View Article : Google Scholar : PubMed/NCBI
28	Thornborrow EC, Patel S, Mastropietro AE, et al: A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene. 21:990–999. 2002. View Article : Google Scholar : PubMed/NCBI
29	Haupt S, Berger M, Goldberg Z and Haupt Y: Apoptosis - the p53 network. J Cell Sci. 116:4077–4085. 2003. View Article : Google Scholar : PubMed/NCBI
30	Yang H, Deng C, Shen S, et al: Expression and significance of Bcl-2, Bax, Fas and caspase-3 in different phases of human hemangioma. J Huazhong Univ Sci Technolog Med Sci. 26:402–404. 2006. View Article : Google Scholar : PubMed/NCBI