共查询到20条相似文献,搜索用时 62 毫秒
1.
The apoptotic effects of 2-amino-4,4alpha-dihydro-4alpha, 7-dimethyl-3H-phenoxazine-3-one (Phx-1) and 2-aminophenoxazine-3-one (Phx-3) on human glioblastoma cell lines, A-172 and U-251 MG were studied. These phenoxazines extensively decreased the viability of A-172 and U-251 MG cells (IC50 of Phx-1: 60 microM, in both lines; IC50 of Phx-3: 10 and 3 microM, for A-172 and U-251 cells, respectively). Phx-1 and Phx-3 increased the population of annexin V and PI double-positive cells in A-172 and U-251 MG cells, resulting in cell death at late stage apoptosis/necrosis. The activities of caspase-3/7 were greatly increased in A-172 and U-251 MG cells treated with Phx-1 or Phx-3. However, a pan-caspase inhibitor, z-VAD-fmk, failed to reverse the antiproliferative and apoptotic effects of Phx-1 and Phx-3 in both cell lines. In conclusion, Phx-1 and Phx-3 exert significant anti-cancer effects against human glioblastoma cell lines, A-172 and U-251 MG, mediated by the caspase-independent apoptotic cell death pathway. 相似文献
2.
背景与目的:粉防己碱(tetrandrine,Tet)是一种天然化合物,其抗视网膜母细胞瘤作用尚不清楚。该研究拟检测Tet对人视网膜母细胞瘤细胞的抗肿瘤作用,并进一步阐明其作用机制。方法:采用CCK-8法检测Tet对视网膜母细胞瘤细胞活力的抑制作用;应用Annexin V/PI法检测细胞凋亡情况;在2’,7’-二氯荧光素二乙酸酯(2’, 7’-dichlorofluorescin diacetate,DCFH-DA)染色后,采用流式细胞术检测细胞内反应性活性氧(reactive oxygen species,ROS)含量;采用蛋白[质]印迹法(Western blot)检测细胞Akt、p-Akt蛋白表达量。结果:Tet显著抑制视网膜母细胞瘤细胞活力,Tet浓度为4、8、10和20 μmol/L处理细胞24 h时,WERI-Rb-1细胞抑制率分别为5.7%、25.0%、55.1%和84.9%,Y79细胞抑制率分别为2.4%、2.9%、23.8%和54.2% (P<0.01);10 μmol/L Tet处理细胞12、24和48 h时,WERI-Rb-1细胞抑制率分别为6.0%、45.5%和74.7%,Y79细胞抑制率分别为2.9%、19.4%和43.3%(P<0.01)。Tet诱导细胞凋亡,以10 μmol/L Tet处理细胞24和48 h时,WERI-Rb-1细胞凋亡率分别为(23.70±1.75)%和(34.83±3.15)%,Y79细胞凋亡率分别为(9.62±2.69)%和(14.97±1.50)%(P<0.01),凋亡抑制剂Z-VAD-FMK能够显著抑制Tet对视网膜母细胞瘤细胞的凋亡诱导作用(P<0.05)。10 μmol/L Tet作用细胞6及12 h后,细胞的ROS产生量较对照组明显上升(P<0.01),N-乙酰基-L-半胱氨酸(N-acetyl-L-cysteine,NAC)能够抑制Tet诱导产生的ROS(P<0.01),NAC抑制ROS后,细胞的凋亡率较单独Tet作用组明显下降(P<0.01)。Tet能够抑制视网膜母细胞瘤细胞PI3K/Akt信号通路。结论:Tet诱导视网膜母细胞瘤细胞凋亡,该作用机制与细胞内ROS升高、PI3K/Akt信号通路抑制有关。 相似文献
3.
Talon I Lindner V Sourbier C Schordan E Rothhut S Barthelmebs M Lang H Helwig JJ Massfelder T 《Carcinogenesis》2006,27(1):73-83
Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in 40-80% of human conventional renal cell carcinomas (RCCs). We showed recently that VHL-deficient RCCs expressed large amounts of parathyroid hormone-related protein (PTHrP), and that PTHrP, acting through the PTH1 receptor (PTH1R), plays an essential role in tumor growth. We also showed that PTHrP expression is negatively regulated by the VHL gene products (pVHL). Our goal was to determine whether blocking the PTHrP/PTH1R system might be of therapeutic value against RCC, independent of VHL status and PTHrP expression levels. The antitumor activity of PTHrP neutralizing antibody and of PTH1R antagonist were evaluated in vitro and in vivo in a panel of human RCC lines expressing or not pVHL. PTHrP is upregulated compared with normal tubular cells. In vitro, tumor cell growth and viability was decreased by up to 80% by the antibody in all cell lines. These effects resulted from apoptosis. Exogenously added PTHrP had no effect on cell growth and viability, but reversed the inhibitory effects of the antibody. The growth inhibition was reproduced by a specific PTH1R antagonist in all cell lines. In vivo, the treatment of nude mice bearing the Caki-1 RCC tumor with the PTHrP antibody inhibited tumor growth by 80%, by inducing apoptosis. Proliferation and neovascularization were not affected by the antiserum. Anti-PTHrP treatment induced no side effects as assessed by animal weight and blood chemistries. Current therapeutic strategies are only marginally effective against metastatic RCC, and adverse effects are common. This study provides a rationale for evaluating the blockade of PTHrP signaling as therapy for human RCC in a clinical setting. 相似文献
4.
In the present study, we investigated the in vitro and in vivo antitumor effects of a sulfated polysaccharide fraction from the brown alga Laminaria japonica (LJSP) on cervical carcinoma. In vitro, the results showed that LJSP exhibited the highest cell growth inhibitory effect on cervical carcinoma U14 cells among five tumor cell lines. In vivo, the results showed that LJSP could not only inhibit the growth of the tumor but also enhance the spleen and thymus indexes, as well as the body weight of U14 tumor-bearing mice. Moreover, the white blood cell count of H22 tumor-bearing mice showed no change in the LJSP-treated groups and little toxicological effects were observed on hepatic function and renal function in LJSP-treated mice bearing U14 tumor cells. Besides, LJSP induced apoptosis of transplanted tumor tissues by increasing the ratio of Bax/Bcl-2. These data showed that LJSP exhibited prominent antitumor activities and low toxic effects; thus, it could be developed to a safe and effective anticancer agent. 相似文献
5.
Vesicular stomatitis virus (VSV) matrix protein (MP) can induce in vitro apoptosis of tumor cells in the absence of other viral components. Here, the antitumor activity of VSV-MP against lung adenocarcinoma was investigated in vivo. A pVAX-plasmid DNA encoding VSV-MP and control empty vectors (pVAX) were constructed and wrapped-up with liposome. A549 and Spc-A1 human lung adenocarcinoma cells were transfected with liposomal-VSV-MP (Lip-MP) or Lip-pVAX and then examined for cell viability or apoptosis using Hoechst/propidium iodide staining by flow cytometry, and further demonstrated by caspase/poly ADP-ribose polymerase (PARP) cleavage analysis. For the in vivo study, A549 and Spc-A1 lung carcinoma models in nude mice were established and randomly assigned into three groups to receive eight 2-weekly intravenous administrations of medium alone as control, Lip-pVAX or Lip-MP, respectively. Subsequently, Lip-MP significantly reduced tumor growth and prolonged the survival of tumor-bearing mice compared with Lip-pVAX and control agents (P<0.05), with much higher apoptosis index of both in vivo and in vitro tumor cells, respectively (P<0.05). In addition, in vivo antitumoral effect was associated with natural killer-(NK) cell congregation without evidence of toxicity. These observations suggest that systemically delivering Lip-MP has a specific dual antitumor activity in human lung adenocarcinoma by inducing apoptosis and possibly stimulating NK-cell responses, it may provide a clue for developing new therapeutic approaches against human lung adenocarcinoma. 相似文献
6.
Kato S Shirato K Imaizumi K Toyota H Mizuguchi J Odawara M Che XF Akiyama S Abe A Tomoda A 《Oncology reports》2006,15(4):843-848
The aim of this study was to investigate the anticancer effects of the phenoxazine derivatives, 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1), 3-amino-1,4alpha-dihydro-4alpha,8-dimethyl-2H-phenoxazine-2-one (Phx-2), and 2-aminophenoxazine-3-one (Phx-3) on human pancreatic cancer cell lines, KLM-1 and MIA-PaCa-2, in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily of cytokines. Of these three phenoxazines, Phx-1 and Phx-3 inhibited proliferation of KLM-1 dose-dependently, but Phx-2 did not. Phx-3 caused both apoptosis and necrosis in KLM-1 cells, as evidenced by the phosphatidylserine externalization and propidium iodide permeable cells detected by a flow cytometric method using annexin-V and propidium iodide. Down-regulation of Bcl-2 expression appeared to be involved in the Phx-3-induced cell death. TRAIL did not affect proliferation of KLM-1, and the inhibitory effects of Phx-1 and Phx-3 on the KLM-1 cell line were not augmented by the combination with TRAIL. On the other hand, proliferation of the MIA-PaCa-2 cell line was not affected by Phx-1, Phx-2 and Phx-3, although it was significantly inhibited by TRAIL in a dose-dependent manner. Inhibitory effects of TRAIL on MIA-PaCa-2 were synergistically augmented by the addition of Phx-1 and Phx-3, but not by Phx-2. These results suggest that both Phx-1 and Phx-3 exert anticancer effects against human pancreatic cancer cells, KLM-1 and MIA-PaCa-2, through distinct action modes. Phx-1 and Phx-3 may be effective for the treatment of pancreatic cancer. 相似文献
7.
Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells 总被引:1,自引:0,他引:1
Ogawa M Nakai S Deguchi A Nonomura T Masaki T Uchida N Yoshiji H Kuriyama S 《International journal of oncology》2007,31(2):323-331
Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a two-color flow cytometric assay using fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, substantially prevented vitamin K-mediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspase-dependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC. 相似文献
8.
Antitumor effects of vitamins K1, K2 and K3 on hepatocellular carcinoma in vitro and in vivo 总被引:8,自引:0,他引:8
Hitomi M Yokoyama F Kita Y Nonomura T Masaki T Yoshiji H Inoue H Kinekawa F Kurokohchi K Uchida N Watanabe S Kuriyama S 《International journal of oncology》2005,26(3):713-720
A number of studies have shown that various K vitamins, specifically vitamins K2 and K3, possess antitumor activity on various types of rodent- and human-derived neoplastic cell lines. In the present study, we examined the antitumor effects of vitamins K1, K2 and K3 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of these vitamins in vitro and in vivo. Although vitamin K1 did not inhibit proliferation of PLC/PRF/5 cells at a 90-microM concentration (the highest tested), vitamins K2 and K3 suppressed proliferation of the cells at concentrations of 90 and 9 microM, respectively. By flow cytometric analysis, it was shown that not only vitamin K1, but also vitamin K2 did not induce apoptosis or cell cycle arrest on PLC/PRF/5 cells. In contrast, vitamin K3 induced G1 arrest, but not apoptosis on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that both vitamins K2 and K3 markedly suppressed the growth of HCC tumors to similar extent. Protein expression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4), but not p16INK4a Cdk inhibitor in the tumor was significantly reduced by vitamin K2 or K3 treatment, indicating that vitamins K2 and K3 may induce G1 arrest of cell cycle on PLC/PRF/5 cells in vivo. Taken collectively, vitamins K2 and K3 were able to induce potent antitumor effects on HCC in vitro and in vivo, at least in part, by inducing G1 arrest of the cell cycle. The results indicate that vitamins K2 and K3 may be useful agents for the treatment of patients with HCC. 相似文献
9.
目的:探讨miR-204在人视网膜母细胞瘤中的表达、临床意义及其分子机制。方法:实时定量PCR检测miR-204在视网膜母细胞瘤及瘤旁组织中的表达并分析其与临床病理特征的关系。检测miR-204在视网膜母细胞瘤细胞系中的表达,并用miR-204模拟物转染Y79细胞,MTT及流式细胞仪检测Y79细胞的增殖、凋亡情况,RT-PCR、Western blot法检测Bcl-2 mRNA、蛋白的表达。结果:miR-204在视网膜母细胞瘤组织中的表达水平显著低于对应瘤旁组织。miR-204低表达与神经浸润、分化程度密切相关。miR-204可显著抑制Y79细胞的增殖并促进其凋亡,下调Bcl-2 mRNA及蛋白表达水平。结论:miR-204在人视网膜母细胞瘤组织中表达下调,并与临床病理相关,miR-204抑制Y79细胞增殖、促进凋亡的作用可能与下调Bcl-2有关。 相似文献
10.
We examined whether phenoxazine derivatives such as 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1) and 2-aminophenoxazine-3-one (Phx-3) may have anticancer effects on the human gastric cancer cell lines, MKN45, MKN74, MKN7 and KATO III in vitro. Phx-1 inhibited the growth of these cancer cells in a dose- and time-dependent manner. The IC50 was approximately 65, 25, 100 and 70 microM for MKN45, MKN74, MKN7 and KATO III respectively, after 72 h. Phx-3 exerted stronger antiproliferative effects against these cancer cells (IC50: approximately 5, 1, 10 and 10 microM for MKN45, MKN74, MKN7 and KATO III, respectively, after 72 h) than Phx-1. Phx-1 and Phx-3 increased the population of TUNEL-positive cells in MKN45 and KATO III time-dependently from 24 to 72 h, suggesting that Phx-1 and Phx-3 have apoptotic activity against these gastric cancer cells. The activity of effector caspase-3 significantly increased in MKN45 treated with Phx-3 for 24 h, but did not altered in the cells treated with Phx-1 for 24 h. When z-VAD-fmk, a pan-caspase inhibitor, was co-treated for 24 h, Phx-3-stimulated caspase-3 activity in MKN45 was reversed to the levels of normal activity, while the antiproliferative and apoptotic effects of Phx-3 against the cells were maintained. The activity of caspase-3 was not activated in KATO III by 24 h exposure for Phx-1 or Phx-3. In conclusion, both phenoxazines prevent the growth of the human gastric cancer cell lines, MKN45 and KATO III in vitro, and cause the apoptosis of these cell lines via a caspase-independent pathway. Although the intracellular action mechanisms of Phx-1 and Phx-3 are still unclear, these phenoxazines may be useful for the treatment of gastric cancer in the future. 相似文献
11.
Potential of traditional ayurvedic formulation, Triphala, as a novel anticancer drug 总被引:1,自引:0,他引:1
The cytotoxic effects of aqueous extract of Triphala, an ayurvedic formulation, were investigated on human breast cancer cell line (MCF-7) and a transplantable mouse thymic lymphoma (barcl-95). The viability of treated cells was found to decrease with the increasing concentrations of Triphala. On the other hand, treatment of normal breast epithelial cells, MCF-10 F, human peripheral blood mononuclear cells, mouse liver and spleen cells, with similar concentrations of Triphala did not affect their cytotoxicity significantly. The drug treatment was found to induce apoptosis in MCF-7 and barcl-95 cells in vitro as determined by annexin-V fluorescence and proportion of apoptotic cells was found dependent on Triphala concentration. MCF-7 cells treated with Triphala when subjected to single cell gel electrophoresis, revealed a pattern of DNA damage, characteristic of apoptosis. Studies on Triphala treated MCF-7 and barcl-95 cells showed significant increase in intracellular reactive oxygen species (ROS) in a concentration dependent manner. ROS increase was, however, found to be insignificant in MCF-10 F as well as in murine spleen and liver normal cells. In vivo, direct oral feeding of Triphala to mice (40 mg/kg body weight) transplanted with barcl-95 produced significant reduction in tumor growth as evaluated by tumor volume measurement. It was also found that apoptosis was significantly higher in the excised tumor tissue of Triphala fed mice as compared to the control, suggesting the involvement of apoptosis in tumor growth reduction. These results suggest that Triphala possessed ability to induce cytotoxicity in tumor cells but spared the normal cells. The differential effect of Triphala on normal and tumor cells seems to be related to its ability to evoke differential response in intracellular ROS generation. The differential response of normal and tumor cells to Triphala in vitro and the substantial regression of transplanted tumor in mice fed with Triphala points to its potential use as an anticancer drug for clinical treatment. 相似文献
12.
The role of adenovirus-mediated retinoblastoma 94 in the treatment of head and neck cancer 总被引:4,自引:0,他引:4
Li D Day KV Yu S Shi G Liu S Guo M Xu Y Sreedharan S O'Malley BW 《Cancer research》2002,62(16):4637-4644
13.
Effect of resveratrol on the development of spontaneous mammary tumors in HER-2/neu transgenic mice 总被引:2,自引:0,他引:2
Provinciali M Re F Donnini A Orlando F Bartozzi B Di Stasio G Smorlesi A 《International journal of cancer. Journal international du cancer》2005,115(1):36-45
Resveratrol (Res) has been reported to possess cancer chemopreventive activity on the basis of its in vitro effects on tumor cells and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of Res on the development of mammary tumors appearing spontaneously in HER-2/neu transgenic mice at an early age. The mechanisms involved in the Res antitumor effect were evaluated by studying the immune effectiveness, tumor apoptosis and expression of mRNA and protein for HER-2/neu in tumoral mammary glands from Res-treated mice and in tumor cell lines. Res supplementation delayed the development of spontaneous mammary tumors (p < 0.001), reduced the mean number and size of mammary tumors (p < 0.0001) and diminished the number of lung metastases in HER-2/neu transgenic mice. The effects of Res were associated with downregulation of HER-2/neu gene expression and increased apoptosis both in tumoral mammary glands and in murine (N202) and human (SKBr3) tumor cell lines. Neither the basal, the IL-2-induced NK activity nor the lymphocyte number and proliferation was modified in Res-supplemented compared to control mice. Our results demonstrate that Res supplementation delays the development and reduces the metastasizing capacity of spontaneous mammary tumors in HER-2/neu transgenic mice. The antitumor effect of Res might be related to the downregulation of HER-2/neu expression and the induction of apoptosis in tumor cells. 相似文献
14.
Shimizu S Suzuki M Miyazawa K Yokoyama T Ohyashiki K Miyazaki K Abe A Tomoda A 《Oncology reports》2005,14(1):41-46
Inhibitory effects of 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1), 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-2) and 2-aminophenoxazine-3-one (Phx-3), which were produced by the reaction of o-aminophenol and its derivatives with bovine hemoglobin, on the proliferation of human malignant melanoma G-361 cells were studied under various conditions. Phx-1 and Phx-3 showed anti-proliferative effects on human malignant melanoma G-361 cells, however Phx-2 did not. Phx-3, which exerted the strongest anti-proliferative effects, inhibited the proliferation of human malignant melanoma G-361 cells during 24 h incubation at concentrations of >or=10 microM. Apoptosis and G1 arrest in the cells, which were detected by DNA laddering on electrophoresis and flow cytometry, respectively, were observed when the melanoma G-361 cells were treated with Phx-3 at 37 degrees C for 24 h. Concomitantly, the increased melanin formation in G-361 cells was indicated by biochemical and morphological detection of melanin within 24 h exposure to Phx-3. The present results suggest that Phx-3 exclusively demonstrates anti-tumor activity against human malignant melanoma G-361 cells by inducing cell cycle accumulation at G1, differentiation and apoptosis. 相似文献
15.
Calvaruso G Carabillò M Giuliano M Lauricella M D'Anneo A Vento R Tesoriere G 《International journal of oncology》2001,18(6):1233-1237
Our results demonstrate that sodium phenylbutyrate, a compound with a low degree of toxicity, exerted a cytotoxic effect on human retinoblastoma Y79 cells in a time- and dose-dependent manner. Treatment of Y79 cells for 72 h with phenylbutyrate reduced cell viability by 63% at 2 mM and 90% at 4 mM. Cell death caused by phenylbutyrate exhibited the typical features of apoptosis, as shown by light and fluorescent microscopy. Western blot analysis demonstrated that exposure of Y79 cells to phenylbutyrate decreased the level of the antiapoptotic factor Bcl-2 and induced the activation of caspase-3, a key enzyme in the execution phase of apoptosis. Moreover, treatment with phenylbutyrate markedly increased the level of acetylated histone-H3. Combined treatment with phenylbutyrate and topotecan, a topoisomerase I-inhibitor, resulted in a clear synergistic effect. We suggest that the effects exerted by phenylbutyrate on Y79 cells essentially depend on modifications of gene expression consequent to histone hyperacetylation. 相似文献
16.
磷酸化JNK介导全反式维甲酸诱导视网膜母细胞瘤细胞凋亡 总被引:1,自引:0,他引:1
目的 探讨全反式维甲酸(ATRA)抑制视网膜母细胞瘤(Rb)细胞生长并诱导其凋亡的作用及信号转导机制。方法 应用^3H—胸腺嘧啶掺人分析法观察ATRA对细胞生长的抑制作用;用流式细胞仪分析ATRA对Y79细胞周期的影响;以DNA片段凝胶电泳分析细胞凋亡;用Western blot分析c—jun氨基末端激酶(JNK)的磷酸化。结果 ATRA可明显抑制Y79细胞的生长,1μmol/L处理36h时,^3H—胸腺嘧啶掺人率下降达40%,Y79细胞被阻滞于G0/G1期,并出现Sub—G1峰。ATRA可诱导Y79细胞凋亡,此凋亡过程可被JNK的阻断剂Curcumin阻断;在此过程中,JNK被激活并磷酸化。结论 ATRA可抑制Y79细胞生长并诱导其凋亡,其过程是由磷酸化的JNK介导,提示ATRA可能是一种潜在的抗Rb化疗药物。 相似文献
17.
PURPOSE: ART and its derivatives, clinically used antimalarial agents, have recently shown antitumor activities. However, the mechanisms underlying these activities remain unclear. This study was designed to determine their antitumor efficacy and underlying mechanisms of action in human hepatoma cells. EXPERIMENTAL DESIGN: The in vitro cytotoxicities of ART, DHA, artemether, and artesunate were compared in human hepatoma cells, HepG2 (p53 wild-type), Huh-7 and BEL-7404 (p53 mutant), and Hep3B (p53 null), and a normal human liver cell line, 7702. Based on their activity and specificity, ART and DHA were further investigated for their in vitro and in vivo antitumor effects and their effects on the protein expression of genes associated with cell proliferation and apoptosis. RESULTS: ART and DHA exerted the greatest cytotoxicity to hepatoma cells but significantly lower cytotoxicity to normal liver cells. The compounds inhibited cell proliferation, induced G(1)-phase arrest, decreased the levels of cyclin D1, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, and E2F1, and increased the levels of Cip1/p21 and Kip1/p27. They induced apoptosis, activated caspase-3, increased the Bax/Bcl-2 ratio and poly(ADP-ribose) polymerase, and down-regulated MDM2. In mice bearing HepG2 and Hep3B xenograft tumors, ART and DHA inhibited tumor growth and modulated tumor gene expression consistent with in vitro observations. DHA increased the efficacy of the chemotherapeutic agent gemcitabine. CONCLUSIONS: ART and DHA have significant anticancer effects against human hepatoma cells, regardless of p53 status, with minimal effects on normal cells, indicating that they are promising therapeutics for human hepatoma used alone or in combination with other therapies. 相似文献
18.
Young Wook Park Maher N Younes Samar A Jasser Orhan G Yigitbasi Ge Zhou Corazon D Bucana Benjamin N Bekele Jeffrey N Myers 《Clinical cancer research》2005,11(5):1963-1973
PURPOSE: We investigated whether concomitant blockade of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways by AEE788, a dual inhibitor of EGFR and VEGFR tyrosine kinases, would inhibit the growth of cutaneous squamous cell carcinoma (SCC) cells and human cutaneous cancer xenografts in nude mice. EXPERIMENTAL DESIGN: We examined the effects of AEE788 on the phosphorylation of EGFR and VEGFR-2 in cutaneous SCC cells expressing EGFR and VEGFR-2 and cutaneous SCC cell growth and apoptosis. We assessed the in vivo antitumor effects of AEE788 in a xenograft model in nude mice. AEE788 (50 mg/kg) was given orally thrice weekly to mice that had been s.c. injected with Colo16 tumor cells. Mechanisms of in vivo AEE788 activity were determined by immunohistochemical analysis. RESULTS: Treatment of cutaneous SCC cells with AEE788 led to dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation, growth inhibition, and induction of apoptosis. In mice treated with AEE788, tumor growth was inhibited by 54% at 21 days after the start of treatment compared with control mice (P < 0.01). Immunohistochemical analysis revealed that AEE788 inhibited phosphorylation of EGFR and VEGFR and induced apoptosis of tumor cells and tumor-associated endothelial cells. CONCLUSIONS: In addition to inhibiting cutaneous cancer cell growth by blocking EGFR and VEGFR signaling pathways in vitro, AEE788 inhibited in vivo tumor growth by inducing tumor and endothelial cell apoptosis. 相似文献
19.
Shiro Soga Sreenath V. Sharma Yukimasa Shiotsu Makiko Shimizu Harunobu Tahara Kazuo Yamaguchi Yoji Ikuina Chikara Murakata Tatsuya Tamaoki Junichi Kurebayashi Theodor W. Schulte Leonard M. Neckers Shiro Akinaga 《Cancer chemotherapy and pharmacology》2001,48(6):435-445
PURPOSE: Radicicol is a novel hsp90 antagonist, distinct from the chemically unrelated benzoquinone ansamycin compounds, geldanamycin and herbimycin. Both geldanamycin and radicicol bind in the aminoterminal nucleotide-binding pocket of hsp90, destabilizing the hsp90 client proteins, many of which are essential for tumor cell growth. We describe here antitumor activity of a novel oxime derivative of radicicol, KF58333. We also investigated the mechanism of antitumor activity of KF58333 in comparison with its oxime isomer KF58332. METHODS: Antiproliferative activities were determined in a panel of breast cancer cell lines in vitro. We also examined inhibition of hsp90 function and apoptosis induction in erbB2-overexpressing human breast carcinoma KPL-4 cells in vitro. Direct binding activity to hsp90 was assessed by hsp90-binding assays using geldanamycin or radicicol beads. In animal studies, we investigated plasma concentrations of these compounds after i.v. injection in BALB/c mice and antitumor activity against KPL-4 cells transplanted into nude mice. Inhibition of hsp90 function and induction of apoptosis in vivo were investigated using tumor specimens from drug-treated animals. RESULTS: KF58333 showed potent antiproliferative activity against all breast cancer cell lines tested in vitro, and was more potent than its stereoisomer KF58332. These results are consistent with the ability of KF58333 to deplete hsp90 client proteins and the induction of apoptosis in KPL-4 cells in vitro. Interestingly, KF58333, but not KF58332, showed significant in vivo antitumor activity accompanied by induction of apoptosis in KPL-4 human breast cancer xenografts. Although the plasma concentrations of these compounds were equivalent, KF58333, but not KF58332, depleted hsp90 client proteins such as erbB2, raf-1 and Akt in the tumor specimen recovered from nude mice. CONCLUSIONS: These results suggest that inhibition of hsp90 function, which causes depletion of hsp90 client proteins in tumor, contributes to the antitumor activity of KF58333, and that the stereochemistry of the oxime moiety is important for the biological activity of radicicol oxime derivatives. 相似文献
20.
A Albini A Melchiori A Garofalo D M Noonan F Basolo G Taraboletti G J Chader R Gavazzi 《International journal of cancer. Journal international du cancer》1992,52(2):234-240
Cells derived from retinoblastomas grow slowly in vitro and only very rarely form tumors in nude mice. Matrigel, a mixture of components normally found in basement membranes, promotes the growth of Y-79 and WERI-Rb1 retinoblastoma (Rb) cells when added to suspension cultures of the 2 Rb cell lines. It also substantially increases cell adhesion in vitro. Y-79 cells, seeded into a Matrigel matrix, form round colonies over a 3-week period similar to those of control, weakly metastatic murine melanoma cells. In vivo, s.c. co-injection of Matrigel with either Y-79 or WERI-Rb 1 cells into nude mice promotes retinoblastoma tumor formation. Transplantation of as few as 1,000 cells allows for xenografting under these conditions, while no tumors were observed in the absence of Matrigel, even at 10 x 10(6) cells/inoculum. The tumors produced have the expected morphology and express an mRNA for a highly specific retina/retinoblastoma marker protein, the interphotoreceptor retinoid-binding protein. Thus, the xenografts obtained maintain the original morphological and molecular characteristics of the injected cells and represent a useful model for in vivo studies of retinoblastoma growth and treatment. 相似文献