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

Abstract

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.

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

“…The effects of PYM on hemangioma-derived endothelial cells have been studied in vitro. PYM treatment (100-300 µg/ml) resulted in a significant and dose-dependent induction of apoptosis in human hemangioma-derived endothelial cells (HemECs) (24). These results were in line with the results of the present study, which showed that PYM inhibited the proliferation of EOMA cells in a dose-and time-dependent manner and significantly induced apoptosis at 100 µg/ml.…”

“…Zhao et al (25) reported that patients with maxillofacial squamous cell carcinomas subjected to microwave-induced hyperthermia followed by intravenous injection of PYM, exhibited an increased number of apoptotic cancer cells; this effect was likely to be mediated via downregulation of Bcl-2 and upregulation of Bax. In HemECs, the induction of apoptosis was attributed to the activation of the p53 pathway (24). The present study demonstrated that the PI3K/Akt pathway has a significant role in PYM-induced inhibition of cell viability and invasive ability as well as induction of apoptosis in EOMA cells.…”

“…Originally, PYM was reported to exert its anti-cancer effects by DNA strand breaks (23). Recent studies have reported mechanisms including activation of the p53 pathway (24), downregulation of B-cell lymphoma 2 (Bcl-2) and upregulation of Bcl-2-associated X protein (Bax) (25) and induction of apoptosis by activation of caspase-3 (26) in vitro and in vivo, which may be downstream cellular responses to PYM treatment. The present study investigated the underlying mechanisms of the anti-cancer activity of PYM on hemangioma by examining its effects on cell viability, cell cycle, invasive potential and the expression of proteins involved in the angiogenesis-associated PI3K/Akt pathway using an MTT assay, flow cytometry, Transwell assay and western blot analysis.…”

Silencing microRNA-143 protects the integrity of the blood-brain barrier: implications for methamphetamine abuse

“…Another novel finding of this study was that PUMA, a newly identified target of miR-143, mediated the expression of TJPs in endothelial cells. As an apoptosis inducer, PUMA has been shown to be involved in the apoptosis of endothelial cells 40 41 . In the current study, methamphetamine failed to affect the apoptosis of endothelial cells ( Supplementary Fig.…”

Efficacy of propranolol and pingyangmycin, respectively, combined with pulsed dye laser on children with hemangioma

“…In recent years, a large number of studies on the successful treatment of hemangioma with oral propranolol have been reported, making propranolol the first-line drug for the treatment of hemangioma (15)(16)(17). Pingyangmycin, as an antitumor antibiotic, forms thrombus in tumor blood sinus and causes fibrosis of the tumor body when injected into a tumor, which is a reliable and effective treatment method for children with hemangioma (18)(19)(20). With the rapid development of laser technology, it has been gradually applied to the treatment of clinical diseases.…”