Aryltetralin lactones featuring vicinal stereogenic centers at their ring junctions are important scaffolds in pharmacologically relevant cyclolignans. Currently, the direct and efficient assembly of tetracyclic core scaffolds from simple acyclic precursors is challenging. Herein, we developed a conformation-assisted radical-initiated iodocarbocyclization of C-(sp3)-H bonds in 5-alkenylmalonates. This was followed by lactonization for the direct assembly of aryltetralin lactone scaffolds. Nine aryltetralin lactone cyclolignans were successfully produced by unified asymmetric total syntheses. This methodology shows potential for advancing both medicinal chemistry and biological research.

Following the publication of the above article, a concerned reader drew to the authors' attention that, among Figs. 1D, 2A and 4B, certain of the control western blots had been re‑used in different blots. The authors have retrieved and re‑examined their original data, and were able to identify the correct control western blots where the data had been inadvertently duplicated in the affected original figures. The revised versions of Figs. 2 and 4, now featuring the correct control western blots, are shown in the subsequent two pages. The authors regret that the data in question featured in the original article had been re‑used, and thank the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 46: 1205‑1213, 2015; DOI: 10.3892/ijo.2014.2800].

Aim To investigate the role of TGF-β3 in the anti-proliferation effect of ursolic acid(UA)in co-lon cancer cells and the possible molecular mechanism underlying this effect.Methods We introduced crys-tal violet staining,flow cytometry and Western blot as-say to determine the effect of UA on proliferation and apoptosis in HCT1 1 6 cells.The levels of TGF-β3, Smad2 /3 and β-catenin in HCT1 1 6 cell were evaluated by RT-PCR and Western blot.Finally,TGF-β3 inhibi-tor and recombinant adenovirus,and luciferase reporter assay were used to analyze the possible mechanism through which TGF-β3 mediated the anti-cancer effect of UA in HCT1 1 6 cells.Results UA inhibited the proliferation and induced apoptosis apparently in HCT1 1 6 cells.UA down-regulated TGF-β3 both in mRNA and in protein level.Meanwhile,UA decreased the phosphorylation of Smad2 /3 concentration depend-ently,although no significant effect was found on the total protein level of Smad2 /3 in HCT1 1 6 cells.Over-expression of TGF-β3 attenuated the inhibitory effect of UA on the proliferation of HCT1 1 6 cells,while the TGF-β3 inhibitor potentiated this effect. UA sup-pressed the transconduction of Wnt/β-catenin signaling in HCT1 1 6 cells through decreasing the level of β-catenin.Exogenous expression of TGF-β3 increased the level of β-catenin and partly reversed the UA-in-duced decrease of β-catenin.However,TGF-β3 inhib-itor potentiated the inhibitory effect of UA on β-catenin in HCT1 1 6 cells.Conclusion The anti-proliferation activity of UA in colon cancer may be partly mediated through down-regulating TGF-β3 to suppress Wnt/β-catenin signaling at least.

目的 研究PTEN对骨形态发生蛋白9(bone morphogenetic protein 9,BMP9)诱导小鼠胚胎成纤维细胞(mouse embryonic fibroblasts,MEFs)成骨分化的影响,并分析PTEN调节BMP9功能的可能机制.方法 采用定量PCR检测PTEN在间充质干细胞(mesenchymal stem cells,MSCs)中的表达,分析在MEFs中BMP9对PTEN表达的影响.采用组织化学染色法检测碱性磷酸酶(alkaline phosphatase,ALP)活性,PCR检测OPN和OCN的表达水平,茜素红染色检测钙盐沉积,分析PTEN对BMP9诱导MEFs成骨分化的影响;利用荧光素酶报告质粒和蛋白印迹等方法分析PTEN对骨形态发生蛋白(bone morphogenetic proteins,BMPs)/Smads信号转导的影响.结果 PTEN在几种常见MSCs中均有表达;BMP9在MEFs中明显抑制PTEN的表达.抑制PTEN能促进BMP9诱导MEFs的ALP活性增加,但过表达PTEN对BMP9诱导MEFs的ALP活性有明显抑制作用.抑制PTEN明显促进BMP9在MEFs细胞中诱导的OCN表达,并增强钙盐沉积.报告质粒分析结果显示,抑制PTEN能明显增强BMPR-Smad报告质粒的转录活性,并增加Smad1/5/8的磷酸化水平.结论 下调PTEN表达可能是BMP9诱导MEFs成骨分化重要途径之一,其机制可能与促进BMPs/Smads信号转导有关.

Objective To determine the anti-proliferative effect of evodiamine( Evo) on colon cancer cells and investigate the possible underlying mechanism. Methods Lo Vo cells were treated with 0,0. 5,1,2and 4 μmol / L Evo,and then the anti-proliferation effect of Evo was assessed by crystal violet staining. Flow cytometry was used to determine the apoptosis of Lo Vo cells after the treatment of 0,0. 5,1 and 2 μmol / L Evo.Western blotting was adopted to detect the expression of proliferating cell nuclear antigen( PCNA) and Caspase-3 in the cells treated with 0,0. 5 and 1 μmol / L Evo. Hypoxia inducible factor 1-alpha( HIF-α)-responsive firefly luciferase reporter was employed to measure the transcription activity of HIF-1α in 0,0. 5,1 and 2 μmol / L Evo treated cells,and Western blotting was used to detect the expression of HIF-1α,Akt1 /2,and p-Akt1 /2in the Lo Vo cells. Results Evo obviously inhibited the proliferation of Lo Vo cells,down-regulated the expression of PCNA and promoted the cell apoptosis. Luciferase reporter system indicated that Evo decreased the transcriptional activity of HIF-1α in a dose-dependent manner( Evo 0. 5 μmol / L,P < 0. 05; 1 or 2 μmol / L,P < 0. 01). Western blotting showed that the expression levels of HIF-1 α and p-Akt1 /2 were reduced after Evo treatment. Conclusion Evo inhibits the proliferation and promotes the apoptosis in Lo Vo cells,which may be due to its down-regulating HIF-1α and inhibiting the transconduction of PI3 K / Akt signaling pathway.

Colon cancer is one of the most common malignancies of the digestive system. Although more effective therapeutic strategies have been developed in the last decades, there is still a great clinical need to explore new treatment regimens for colon cancer due to the undesirable prognosis. In the present study, we investigated the anticancer activity of resveratrol (Res) in human colon cancer cells, and the possible mechanism underlying this effect. We employed crystal violet staining, flow cytometry and western blotting to test the antiproliferation- and apoptosis-inducing effects of Res in LoVo cells. A xenograft tumor model was also introduced to confirm the in vivo anticancer effect of Res. Using PCR, western blotting, a recombinant adenovirus and a specific inhibitor of p38 MAPK or bone morphogenetic protein receptor (BMPR) to explore the possible molecular mechanisms. We found that Res markedly inhibited the proliferation and promoted the apoptosis of LoVo cells, and suppressed the in vivo tumor growth of colon cancer. Res substantially upregulated the expression of bone morphogenetic protein 9 (BMP9). Exogenous expression of BMP9 enhanced the anticancer effect of Res in LoVo cells, while BMP9 knockdown partly reduced this activity. Res increased the activation of p38 MAPK, which was enhanced by the exogenous expression of BMP9. The anticancer activity of Res, or Res combined with BMP9, was reduced partly by the p38 MAPK inhibitor. The BMPR inhibitor almost abolished the Res-induced activation of p38 MAPK, and attenuated the antiproliferative effect of Res in the LoVo cells. Our findings strongly suggest that the anticancer effect of Res in human colon cancer cells may be partly mediated by upregulation of BMP9 to activate p38 MAPK in a BMPR-dependent manner.

Aim To investigate the anti-proliferating&nbsp;effect of tetrandrine ( Tet ) on colon cancer cells and its&nbsp;possible molecular mechanism. Methods We intro-duced crystal violet staining and flow cytometry to ana-lyze the effect of Tet on proliferation in LoVo cells. Flow cytometry was used to detect the effect of Tet on apoptosis in LoVo cells. Western blot assay was taken to analyze the effect of Tet on the expression of insulin-like growth factor binding protein 5 ( IGFBP5 ) . Final-ly, luciferase reporter assay, recombinant adenovirus mediated over-expression or silence of IGFBP5 were used to analyze the possible role of IGFBP5 in the anti-proliferating effect of Tet on colon cancer cells. Re-sults Crystal violet staining and flow cytometery anal-ysis results showed that Tet could exert an anti-prolifer-ating effect and induce apoptosis in LoVo cells. Tet de-creased the expression of IGFBP5 in a concentration-dependent manner. Tet inhibited the transcriptional ac-tivity of pTOP-luc reporter, which could be reversed by exogenous expression of IGFBP5 mostly. Similar results were found in the expression of c-Myc, but IGFPB5 knockdown couldn’ t reverse this effect. Conclusion Tet can inhibit the proliferation of colon cancer cells, and this effect may be mediated by down-regulating the expression of IGFBP5 to inhibit Wnt/β-catenin signa-ling transduction partly.

Colon cancer is one of the most common malignancies, causes considerable morbidity and mortality. The current treatment for colon cancer is more modest than had been hoped. There is an urgent clinical need to explore new agents or adjuvants for colon cancer treatment. Natural products and their derivates act as one of the major source for anticancer agent. In the present study, we investigated the anti-proliferation and chemoprevention effects of tetrandrine (Tet) on colon cancer cells to uncover the possible molecular basis of this effect. We found that Tet can inhibit proliferation and induce apoptosis in LoVo cells. With dimethylhydrazine (DMH) and dextran sodium sulfate (DSS) induced colon cancer model, we found that Tet can prevent or inhibit DMH plus DSS induced aberrant crypt foci (ACF) and colon cancer formation, as well as suppress tumor growth in the xenograft colon cancer model. Tet can downregulate the expression of IGFBP-5 in LoVo cells. Exogenous expression of IGFBP-5 can attenuate the anti-cancer activity of Tet, while IGFBP-5 knockdown potentiates this effect of Tet on LoVo cells. Tet can inhibit Wnt/β-catenin signaling transduction, which can be partly reversed by exogenous expression of IGFBP-5, but is enhanced by IGFBP-5 knockdown. Our results demonstrated that the anticancer activity of Tet in colon cancer cells may be mediated partly by downregulating the expression of IGFBP-5, thus inactivating Wnt/β-catenin signaling transduction.

目的 研究白藜芦醇(resveratrol,Res)对人结肠癌细胞增殖的抑制作用及可能的机制.方法 采用结晶紫染色、流式细胞术和Western blot分析Res对HCT116细胞增殖的抑制作用;应用流式细胞术和免疫荧光分析Res对HCT116细胞凋亡的促进作用;采用Western blot和PCR分析Res对HCT116细胞内Aktl/2及PTEN表达水平的影响;通过重组腺病毒介导的PTEN过表达或沉黙表达,分析Res抑制HCT116细胞增殖及其与PTEN的关系.结果 与对照组相比,Res处理组HCT116细胞增殖受到抑制(P ＜0.05,P＜0.01),G1期细胞比例也随Res浓度增加而升高,同时PCNA蛋白表达水平下降;流式细胞术分析结果显示,Res能明显促进HCT116细胞凋亡;Western blot和PCR分析结果显示,Res对Akt1/2 mRNA表达无明显影响,但能降低Akt 1/2的磷酸化水平,同时促进PTEN表达.外源性过表达PTEN能增强Res对HCT116细胞的增殖抑制作用(P＜0.01),而沉黙PTEN表达能部分逆转Res对HCT116细胞增殖的抑制作用(P＜0.01).结论 Res对HCT116细胞增殖具有抑制作用,并能促进其凋亡;Res的这种作用可能与其促进PTEN表达,抑制PI3K/Akt活化有关.

Colon cancer is one of the most common malignancies. Although the current treatment regimes for colon cancer have been well-developed in the past decades, the prognosis remains still undesirable. It is still urgent to explore new treatment strategies for colon cancer. Natural products is one of the most useful sources for anticancer agents, although some of them have serious side-effects. Evodiamine (Evo) is an quinolone alkaloid from the traditional herb medicine Evodia rutaecarpa. In the present study, we investigated the anticancer effect of Evo in human colon cancer cells. We found that Evo exhibits prominent antiproliferation and apoptosis inducing effects in LoVo cells. Evo leads to apparent downregulation of HIF-1α either in vitro or in vivo; exogenous expression of HIF-1α can attenuate the antiproliferation effect of Evo in LoVo cells, while HIF-1α knockdown potentiates this effect greatly. Further analysis indicated that Evo can also inhibit the phosphorylation of Akt1/2/3 and decrease greatly the expression of IGF-1. Thus, our findings strongly suggested that the anticancer effect of Evo in human colon cancer may be partly mediated by downregulating HIF-1α expression, which is initiated by inactivating PI3K/Akt signaling transduction though decreasing the expression of IGF-1 in colon cancer cells. Therefore, Evo may be used alone or in combination as a potential anticancer agent for colon cancer treatment.

Colon cancer is one of the most common malignancies and the treatments for colon cancer have been developed substantially in the last decades, but there is still a great clinical need to explore new treatment regimens due to the undesirable prognosis. In this investigation, we demonstrated the anti-proliferative and apoptosis-inducing activities of resveratrol (Res) in human colon cancer cells, and the possible mechanisms underlying these effects. We used crystal violet staining, flow cytometry and western blotting to validate the anti-proliferative and apoptosis-inducing effects of Res on HCT116 cells. A xenograft tumor model was used to confirm the anti-proliferative effects of Res. We employed polymerase chain reaction, western blotting, recombinant adenovirus and luciferase reporter assay to explore the possible mechanism(s) of action. We found that Res inhibits significantly the proliferation and promotes apoptosis in HCT116 cells, as well as inhibits the xenograft tumor growth of colon cancer. Res upregulates the expression of phosphatase and tensin homolog (PTEN) and decreases the phosphorylation of Akt1/2. The exogenous expression of PTEN inhibits the PI3K/Akt signal and promotes the anti-proliferative effects of Res in HCT116 cells, while knockdown of PTEN increases PI3K/Akt signal but reduces the anti-proliferative function of Res. The protein and mRNA expression of β-catenin are all decreased by Res concentration-dependently. Thus, our findings strongly suggest that the anti-proliferative effects of Res in human colon cancer cells may be mediated by regulating separately the PTEN/PI3K/Akt and Wnt/β-catenin signaling.

Aim To investigate the role of COX-2 in BMP9 induced osteogenic differentiation,and the pos-sible mechanism underlying this function of COX-2. Methods We introduced real-time PCR, Western blot, and immunocytochemical staing to detect the effect of BMP9 on COX-2 expression.We employed chemiluminescence technique to assay ALP activities, RT-PCR to detect the expression of Smad6 and Smad7 , and Western blot to measure the expression of Runx2, Dlx-5,total Smad1/5/8,and phosphorylated Smad1/5/8.Finally,BMPR-Smad luciferase reporter assay was applied to measure the activation of BMPs/Smads signaling.Results BMP9 could induce the expression of COX-2 in C3H10T1/2 cells.Either inhibiting enzy-matic activity of COX-2 or knockdown of the expression of COX-2 reduced the BMP9 induced ALP activities in C3H10T1/2 cells,and COX-2 knockdown also inhibited the ectopic bone formation induced by BMP9 in C3H10T1/2 cells.Moreover,COX-2 knockdown inhibi-ted BMPR-Smad reporter activities and the phosphoryl-ation of Smad1/5/8,so did the expression of Smad6 and Smad7 .Conclusion COX-2 may play an impor-tant role in BMP9 induced osteogenic differentiation in MSCs by regulating the BMPs/Smads signaling trans-duction.

Mouse embryonic fibroblasts (MEFs) are multi-potent progenitor cells (MPCs), can differentiate into different lineages, such as osteogenic, and adipogenic. PTEN, a tumor suppressor, may be involved in regulating bone development through interacting with COX-2. BMP9, the most potent osteogenic BMPs, can up-regulate COX-2 in MPCs. Whether PTEN is involved in BMP9 induced osteogenic differentiation in MPCs remains unknown. The goal of this investigation is to identify the effect of PTEN on BMP9-induced osteogenic differentiation in MPCs and dissect the possible mechanism underlay this. We found that BMP9 down-regulates PTEN, and PTEN inhibitor (VO) effectively increases different osteogenic markers induced by BMP9 in MEFs. Exogenous expression of PTEN inhibits BMP9 induced ectopic bone formation apparently. Mechanistically, we found that VO can enhance BMP9 induced BMPs/Smads signaling prominently without no substantial effects on cell cycle. Further analysis indicates that VO can promote BMP9-induced expression of COX-2 in MEFs, which can be eliminated by PI3K inhibitor. Additionally, COX-2 knockdown abolishes the effect of VO on BMP9-induced ALP activities in MEFs. Our findings suggest that PTEN plays an important role in regulating BMP9 induced osteogenic differentiation in MPCs, which may be mediated by PTEN/PI3K/Akt signaling to modulate the expression of COX-2.