The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II. Conversely, knockdown of RNF4 led to a remarkable increase in PML SUMOylation and the function of PML-NBs, further promoting ATO- or Ang II-induced HERG protein downregulation. Mechanistically, an increase in PML SUMOylation by ATO or Ang II dramatically enhanced the formation of PML and Pin1 complexes in PML-NBs, leading to the upregulation of TGF-β1 protein, eventually inhibiting HERG expression through activation of protein kinase A. The present work uncovered a novel molecular mechanism underlying HERG protein expression and indicated that PML SUMOylation is a critical step in the development of drug-acquired arrhythmia.

Self-assembled micelles of amphiphilic PEG-rapamycin conjugates loaded with paclitaxel have been developed for co-delivery and simultaneous intracellular release of paclitaxel and rapamycin, bypassing the cancer cell drug resistant mechanism and maximising the synergy of dual-drug combinational therapy. This novel nanomedicine offers 20-fold improved potency over free paclitaxel against a model multidrug resistant human breast cancer cell.

Arsenic sulfide (As4S4) is the main component of realgar, which is widely used in traditional Chinese medicine. Previous studies have shown the beneficial effects of As4S4 in the treatment of hematological malignant diseases, however, its effects on solid tumors have yet to be fully elucidated. The current study aimed to explore the anti‑cancer effect and the mechanism of As4S4 on solid tumors in vitro and in vivo. Cells from four human solid tumor cell lines, including the MKN45 gastric cancer cell line, the A375 malignant melanoma cell line, the 8898 pancreatic carcinoma cell line and the HepG2 hepatocellular carcinoma cell line, were treated with As4S4 in vitro, using the L02 embryonic liver cells as a control. The efficacy of As4S4 was assessed in vivo using mice implanted with Lewis lung carcinoma cells. The results of the current study demonstrated that As4S4 significantly inhibited the proliferation of solid tumor cells in a dose‑ and time‑dependent manner, but produced a less pronounced effect on L02 cells. Additionally, As4S4 was observed to induce apoptosis (including morphological changes and an enhanced sub‑G1 population), which was accompanied by the activation of caspase‑3 and ‑9. Furthermore, treatment with As4S4 significantly inhibited the growth of implanted tumors in mice. These results suggest that As4S4 possesses potent in vitro and in vivo antitumor activity via the induction of cell apoptosis.

A paclitaxel loaded PEGylated rapamycin micelle effectively bypasses the resistance mechanism, allowing for potent treatment of multidrug resistant cancer cells.

目的:研究冬凌草甲素(ORI)对人结肠癌细胞株HCT116生长的影响及其可能机制.方法:以体外培养的HCT116细胞为研究对象,给予不同浓度(0、2.5、5、10、20 μ M)ORI处理HCT116细胞不同时间(0、24、48、72h),通过MTT法检测其对HCT116细胞增殖的影响,DAPI染色观察其对细胞核的形态的影响,western blot检测细胞内β-catenin、c-myc蛋白表达的变化.结果:①ORI可显著抑制HCT116细胞的增殖,且此作用随着浓度和作用时间的增加或延长而增强(P＜0.05).②ORI处理HCT116细胞24小时后,细胞核固缩的百分率随药物作用浓度的增加而增加.③5、10、20μM ORI处理HCT116细胞24小时后,细胞内的β-catenin、c-myc蛋白水平均显著下调,且随着ORI浓度的增加逐渐减少.结论:ORI能以浓度和时间依赖性的方式抑制HCT116细胞的增殖,其机制可能与Wnt/β-catenin信号通路有关.

Angiogenesis is an integral process in carcinogenesis, and molecular inhibitors of angiogenic factors are currently being tested as treatments for cancer. Sunitinib is an oral multitargeted tyrosine-kinase inhibitor that blocks activation through the stem cell-factor receptor (Kit) and platelet-derived growth-factor receptor. Sunitinib has shown potent antitumor activity against several solid tumors, including renal cell carcinoma, gastrointestinal stromal tumors, and neuroendocrine tumors in several Phase II/III trials. Recently, sunitinib has been used to treat other solid cancers, such as lung cancer, pancreatic cancer, chondrosarcoma, esophageal cancer, bladder cancer, glioma, and aggressive fibromatosis, and also showed potential efficacy in progression-free survival and overall survival. In this review, we examine the efficacy of sunitinib as a molecular-targeted therapy in patients with different types of solid cancers.

Background: Arsenic sulfide (As4S4), the main component of realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types, especially for acute promyelocytic leukemia. In this study, we aimed to explore the efficacy and mechanism of As4S4 in gastric cancer.Methods: The effect of As4S4 on cell proliferation and apoptosis of gastric cancer cells was investigated by MTT assay, 4', 6-diamidino-2-phenylindole (DAPI) staining, and annexin V-fluorescein isothiocyanate/propidium iodide staining using gastric cancer cell lines AGS (harboring wild-type p53) and MGC803 (harboring mutant p53) in vitro. The expression of apoptosis-related proteins was measured by Western blotting, real-time polymerase chain reaction, and immunohistochemistry analysis. Mouse xenograft models were established by inoculation with MGC803 cells, and the morphology and the proportion of apoptotic cells in tumor tissues were detected by hematoxylin and eosin staining and TdT-mediated dUTP nick end labeling (TUNEL) assay, respectively.Results: As4S4 inhibited the proliferation and induced apoptosis of AGS and MGC803 cells in a time- and dose-dependent manner. As4S4 upregulated the expression of Bax and MDM2 while downregulated the expression of Bcl-2. The expression of p53 increased significantly in the AGS cells but did not readily increase in the MGC803 cells, which harbored mutant p53. Pifithrin-alpha, a p53 inhibitor, blocked the modulation of As4S4 on AGS cells, but not on MGC803 cells. Using xenograft as a model, we showed that As4S4 suppressed tumor growth and induced apoptosis in vivo and that the expression of p53 increased accordingly.Conclusion: As4S4 is a potent cytotoxic agent for gastric cancer cells, as it induced apoptosis both in vitro and in vivo through a p53-dependent pathway. Our data indicate that As4S4 may have therapeutic potential in gastric cancer.

Objective:To investigate the role of realgar(As4S4) on regulating migration ability of HCT116 cells in vitro.Methods:The cytotoxicity effect of As4S4 on HCT116 cells was observed by MTT assay.The effect of As4S4 on migration ability was observed by cell migration test.Expression of E-cadherin,P53 and Notch1 protein and mRNA levels was determined by western blot assay and Real-time PCR assay.Results:The proliferation of HCT116 cells was inhibited by As4S4 in a dose-dependent manner.1 μM As4S4 showed no significant proliferation inhibition effect on HCT116 cells.With this dose,As4S4 reduced the migration ability of HCT116 cells by 52.00%±7.55%.As4S4 treatment up-regulated the protein and mRNA levels of E-cadherin,up-regulated the protein level of P53,but showed no effect on Notch1.Conclusion:As4S4 reduced the proliferation and migration ability of HCT116 cells.Inhibition of the migra-tion ability probably caused by the up-regulation of P53 and E-cadherin.

Objective: To investigate the effect of Arsenic Sulfide(As4 S4) on human acute T-cell leukemia cell line Jurkat and its mechanism.Methods: Jurkat cells were treated with Arsenic Sulfide in various concentrations(0,2.5,5,10,20 μM) for different durations(24,48 and 72 h).The inhibitive effect of Arsenic Sulfide on growth was detected by MTT method.The morphological changes and number of cells incubated with Arsenic Sulfide(0,5,10,20 μM) for 24 hours were observed under the inverted microscope.The expression of Cleaved Notch1 protein and C-myc protein was assayed by western blot after Jurkat cells were treated with Arsenic Sulfide in various concentrations(0,5,10 μM) for 24 hours.Results: ①The results of MTT showed Jurkat cell proliferation was inhibited in a time and concentration dependent manner after treatment of Arsenic Sulfide(P0.05).②As the drug concentration increased,the number of cells decreased while cell fragments increased.③Western blot assay indicated the expression of Cleaved Notch1 protein and C-myc protein reduced in Jurkat cells treated with Arsenic Sulfide for 24 hours.Conclusion: Arsenic Sulfide could inhibit Jurkat cell proliferation and the mechanism may be involved in Notch pathway.

Oridonin, a diterpenoid isolated from Rabdosia rubescens, has been proven to possess various pharmacological and physiological effects such as anti-inflammation, anti-bacterial, and anti-neoplastic, although in recent years, more attention has been paid to its anti-neoplastic effects. For example, oridonin can trigger cell cycle arrest, apoptosis, and autophagy in different neoplastic cell lines. This review summarizes the considerable knowledge about the action mechanisms of oridonin that has been studied in recent years. The present observations reveal the novel anti-neoplastic effects of oridonin, suggesting that it may be effective as a potent alternative or adjunct drug to conventional chemotherapy.