Phosphoinositide 3-kinase/Akt pathway is involved in pingyangmycin‑induced growth inhibition, apoptosis and reduction of invasive potential in EOMA mouse hemangioendothelioma cells

Peng,Li‑Xia; Zhao,Ping; Zhao,Hong‑Sheng; Pan,Er; Yang,Bin‑Bin; Li,Qin

doi:10.3892/mmr.2015.4447

Phosphoinositide 3-kinase/Akt pathway is involved in pingyangmycin‑induced growth inhibition, apoptosis and reduction of invasive potential in EOMA mouse hemangioendothelioma cells

Authors:
- Li‑Xia Peng
- Ping Zhao
- Hong‑Sheng Zhao
- Er Pan
- Bin‑Bin Yang
- Qin Li
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Affiliations: Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Breast Surgery, The Third Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650000, P.R. China, Department of General Surgery, The Second People's Hospital of Dehong, Dehong, Yunnan 678400, P.R. China, Department of Dermatology, The Second Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650000, P.R. China
Published online on: October 15, 2015 https://doi.org/10.3892/mmr.2015.4447
Pages: 8275-8281

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Abstract

Pingyangmycin (PYM), a glycopeptide antibiotic, has been recommended as a stand treatment for hemangioma. However, the underlying mechanisms of its anti‑tumor effects have remained elusive. The purpose of the present study was to explore the effects of PYM on the biological behavior of the EOMA mouse hemangioendothelioma cell line and investigate the possible mechanisms. The effects of PYM on EOMA cell viability were determined by an MTT assay, apoptosis was evaluated by Annexin V/propidium iodide staining and flow cytometric analysis, and cell invasion ability was determined using a Transwell invasion assay. In order to investigate the underlying mechanism of action of PYM, the expression of angiogenic signaling proteins was determined by western blot analysis. PYM treatment (0.5‑500 µg/ml) inhibited cell growth in a time- and dose‑dependent manner. PYM at 100 µg/ml significantly induced apoptosis and reduced the invasive ability of EOMA cells. Effects of PYM on cell viability, apoptosis and invasion ability were completely blocked by co‑treatment with phosphoinositide 3‑kinase (PI3K) activator insulin‑like growth factor‑1 (IGF‑1). Furthermore, treatment with PYM reduced the expression of PI3K and phosphorylated Akt. In conclusion, the present study indicated that the PI3K/Akt pathway is likely to be involved in the anti-cancer effects of PYM on EOMA cells.

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1	Meisheng X: Histopathologic study of esophageal squamous cell carcinoma treated preoperatively with Pingyangmycin. Chin Med J (Engl). 92:343–348. 1979.
2	Zheng JW, Zhou Q, Yang XJ, He Y, Wang YA, Ye WM, Zhu HG and Zhang ZY: Intralesional injection of Pingyangmycin may be an effective treatment for epulis. Med Hypotheses. 72:453–454. 2009. View Article : Google Scholar : PubMed/NCBI
3	Liang XH, He YW, Tang YL, Wu JL, Cao XP, Xiao GZ and Mao ZY: Thermochemotherapy of lower lip squamous cell carcinoma without metastases: An experience of 31 cases. J Craniomaxillofac Surg. 38:260–265. 2010. View Article : Google Scholar
4	Guan JY, He XF, Chen Y, Zeng QL, Mei QL and Li YH: 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
5	Qi W, Guo J, Wu S, Su B, Zhang L, Pan J and Zhang J: Synergistic effect of nanosecond pulsed electric field combined with low-dose of pingyangmycin on salivary adenoid cystic carcinoma. Oncol Rep. 31:2220–2228. 2014.PubMed/NCBI
6	Bai N, Chen YZ, Fu YJ, Wu P and Zhang WN: A clinical study of pingyangmycin sclerotherapy for venous malformation: An evaluation of 281 consecutive patients. J Clin Pharm Ther. 39:521–526. 2014. View Article : Google Scholar : PubMed/NCBI
7	Jia R, Xu S, Huang X, Song X, Pan H, Zhang L, He F, Lin M, Ge S and Fan X: Pingyangmycin as first-line treatment for low-flow orbital or periorbital venous malformations: Evaluation of 33 consecutive patients. JAMA Ophthalmol. 132:942–948. 2014. View Article : Google Scholar : PubMed/NCBI
8	Yue H, Qian J, Elner VM, Guo J, Yuan YF, Zhang R and Ge Q: Treatment of orbital vascular malformations with intralesional injection of pingyangmycin. Br J Ophthalmol. 97:739–745. 2013. View Article : Google Scholar : PubMed/NCBI
9	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
10	Luo Q and Zhao F: How to use bleomycin A5 for infantile maxillofacial haemangiomas: Clinical evaluation of 82 consecutive cases. J Craniomaxillofac Surg. 39:482–486. 2011. View Article : Google Scholar
11	Hou J, Wang M, Tang H, Wang Y and Huang H: 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
12	Yang Y, Sun M, Cheng X, Hu X, Zhang P, Ma Q, Li J, Tian L and Lei D: Bleomycin A5 plus dexamethasone for control of growth in infantile parotid hemangiomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 108:62–69. 2009. View Article : Google Scholar : PubMed/NCBI
13	Zheng JW, Zhou Q, Yang XJ, Wang YA, Fan XD, Zhou GY, Zhang ZY and Suen JY: Treatment guideline for hemangiomas and vascular malformations of the head and neck. Head Neck. 32:1088–1098. 2010. View Article : Google Scholar
14	Greenberger S and Bischoff J: Infantile hemangioma-mechanism(s) of drug action on a vascular tumor. Cold Spring Harb Perspect Med. 1:a0064602011. View Article : Google Scholar
15	Greenberger S and Bischoff J: Pathogenesis of infantile haemangioma. Br J Dermatol. 169:12–19. 2013. View Article : Google Scholar : PubMed/NCBI
16	Verheul HM and Pinedo HM: The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGF-receptor kinase inhibitors. Clin Breast Cancer. 1(Suppl 1): S80–S84. 2000. View Article : Google Scholar
17	Boye E and Olsen BR: Signaling mechanisms in infantile hemangioma. Curr Opin Hematol. 16:202–208. 2009. View Article : Google Scholar : PubMed/NCBI
18	Augustin HG, Koh GY, Thurston G and Alitalo K: Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 10:165–177. 2009. View Article : Google Scholar : PubMed/NCBI
19	Phng LK and Gerhardt H: Angiogenesis: A team effort coordinated by notch. Dev Cell. 16:196–208. 2009. View Article : Google Scholar : PubMed/NCBI
20	Bauer TM, Patel MR and Infante JR: Targeting PI3 kinase in cancer. Pharmacol Ther. 146:53–60. 2015. View Article : Google Scholar
21	Phung TL, Eyiah-Mensah G, O'Donnell RK, Bieniek R, Shechter S, Walsh K, Kuperwasser C and Benjamin LE: Endothelial Akt signaling is rate-limiting for rapamycin inhibition of mouse mammary tumor progression. Cancer Res. 67:5070–5075. 2007. View Article : Google Scholar : PubMed/NCBI
22	Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, et al: Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat Med. 8:128–135. 2002. View Article : Google Scholar : PubMed/NCBI
23	Tai KW, Chang YC, Chou LS and Chou MY: Cytotoxic effect of pingyangmycin on cultured KB cells. Oral Oncol. 34:219–223. 1998. View Article : Google Scholar : PubMed/NCBI
24	Tu JB, Li QY, Jiang F, Hu XY, Ma RZ, Dong Q, Zhang H, Pattar P and Li SX: Pingyangmycin stimulates apoptosis in human hemangioma-derived endothelial cells through activation of the p53 pathway. Mol Med Rep. 10:301–305. 2014.PubMed/NCBI
25	Zhao J, Wang SZ, Tang XF, Liu N, Zhao D and Mao ZY: Analysis of thermochemotherapy-induced apoptosis and the protein expressions of Bcl-2 and Bax in maxillofacial squamous cell carcinomas. Med Oncol. 28(Suppl 1): S354–S359. 2011. View Article : Google Scholar
26	Huang Y, Li P, Xia S, Zhuo Y and Wu L: Proapoptotic effect and the mechanism of action of pingyangmycin on cavernous hemangiomas. Exp Ther Med. 7:473–477. 2014.PubMed/NCBI
27	Tai KW, Chou MY, Hu CC, Yang JJ and Chang YC: Induction of apoptosis in KB cells by pingyangmycin. Oral Oncol. 36:242–247. 2000. View Article : Google Scholar : PubMed/NCBI
28	Yang LC, Yang SH, Tai KW, Chou MY and Yang JJ: MEK inhibition enhances bleomycin A5-induced apoptosis in an oral cancer cell line: Signaling mechanisms and therapeutic opportunities. J Oral Pathol Med. 33:37–45. 2004. View Article : Google Scholar
29	Fruman DA and Rommel C: PI3K and cancer: Lessons, challenges and opportunities. Nat Rev Drug Discov. 13:140–156. 2014. View Article : Google Scholar : PubMed/NCBI
30	Hassan B, Akcakanat A, Holder AM and Meric-Bernstam F: Targeting the PI3-kinase/Akt/mTOR signaling pathway. Surg Oncol Clin N Am. 22:641–664. 2013. View Article : Google Scholar : PubMed/NCBI
31	Khan KH, Yap TA, Yan L and Cunningham D: Targeting the PI3K-AKT-mTOR signaling network in cancer. Chin J Cancer. 32:253–265. 2013. View Article : Google Scholar : PubMed/NCBI
32	Sun SY: MTOR kinase inhibitors as potential cancer therapeutic drugs. Cancer Lett. 340:1–8. 2013. View Article : Google Scholar : PubMed/NCBI
33	Alessi DR, Pearce LR and Garcia-Martinez JM: New insights into mTOR signaling: MTORC2 and beyond. Sci Signal. 2:pe272009. View Article : Google Scholar : PubMed/NCBI
34	Zheng NN, Ding XD and Zhang HP: Targeting rictor inhibits mouse vascular tumor cell proliferation and invasion in vitro and tumor growth in vivo. Neoplasma. 60:41–45. 2013. View Article : Google Scholar
35	Aouida M and Ramotar D: A new twist in cellular resistance to the anticancer drug bleomycin-A5. Curr Drug Metab. 11:595–602. 2010. View Article : Google Scholar : PubMed/NCBI
36	Raisfeld IH: Pulmonary toxicity of bleomycin analogs. Toxicol Appl Pharmacol. 56:326–336. 1980. View Article : Google Scholar : PubMed/NCBI
37	Russo RC, Garcia CC, Barcelos LS, Rachid MA, Guabiraba R, Roffê E, Souza AL, Sousa LP, Mirolo M, Doni A, et al: Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice. J Leukoc Biol. 89:269–282. 2011. View Article : Google Scholar
38	Wei X, Han J, Chen ZZ, Qi BW, Wang GC, Ma YH, Zheng H, Luo YF, Wei YQ and Chen LJ: A phosphoinositide 3-kinase-gamma inhibitor, AS605240 prevents bleomycin-induced pulmonary fibrosis in rats. Biochem Biophys Res Commun. 397:311–317. 2010. View Article : Google Scholar : PubMed/NCBI