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tRNA Binding to Antitumor Drug Doxorubicin and Its Analogue  [PDF]
Daniel Agudelo, Philippe Bourassa, Marc Beauregard, Gervais Bérubé, Heidar-Ali Tajmir-Riahi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069248
Abstract: The binding sites of antitumor drug doxorubicin (DOX) and its analogue N-(trifluoroacetyl) doxorubicin (FDOX) with tRNA were located, using FTIR, CD, fluorescence spectroscopic methods and molecular modeling. Different binding sites are involved in drug-tRNA adducts with DOX located in the vicinity of A-29, A-31, A-38, C-25, C-27, C-28, G-30 and U-41, while FDOX bindings involved A-23, A-44, C-25, C-27, G-24, G-42, G-53, G-45 and U-41 with similar free binding energy (-4.44 for DOX and -4.41 kcal/mol for FDOX adducts). Spectroscopic results showed that both hydrophilic and hydrophobic contacts are involved in drug-tRNA complexation and FDOX forms more stable complexes than DOX with KDOX-tRNA = 4.7 (±0.5)×104 M?1 and KFDOX-tRNA = 6.3 (±0.7)×104 M?1. The number of drug molecules bound per tRNA (n) was 0.6 for DOX and 0.4 for FDOX. No major alterations of tRNA structure were observed and tRNA remained in A-family conformation, while biopolymer aggregation and particle formation occurred at high drug concentrations.
Stat3 Inhibitor Stattic Exhibits Potent Antitumor Activity and Induces Chemo- and Radio-Sensitivity in Nasopharyngeal Carcinoma  [PDF]
Yunbao Pan, Fuling Zhou, Ronghua Zhang, Francois X. Claret
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054565
Abstract: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia, Africa and Alaska. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin and radiotherapy. Signal transducer and activator of transcription 3 (Stat3) has been implicated in the development and progression of various solid tumors. In this study, we assessed the activation and expression of Stat3 in NPC cells. We found that Stat3 was activated and could be blocked by the small molecule inhibitor Stattic. The inhibition of Stat3 in NPC cells by Stattic decreased the expression of cyclin D1 in a dose- and time-dependent manner. Thus, Stattic was used to target Stat3 in NPC cell lines. We found that Stattic could inhibit cell viability and proliferation in NPC cells and significantly induced apoptosis. Additionally, Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of Stattic upon cell viability inhibition and apoptosis induction. Furthermore, Stattic sensitized NPC cells to cisplatin and ionizing radiation (IR) by preventing cell proliferation and inducing apoptosis. Taken together, Stattic inhibit Stat3 and display antitumor effect in NPC, and enhanced chemosensitivity and radiosensitivity in NPC. Therefore, our findings provide the base for more rational approaches to treat NPC in the clinic.
socs3通过jnk和stat3信号通路调控akt  [PDF]
周立军,刘文娟,祁永浩,李妙
中国生物工程杂志 , 2015,
Abstract: 蛋白激酶b(akt),在细胞存活、代谢、迁移和侵袭等信号通路中起着重要的调控作用.细胞信号转导抑制因子3(socs3)主要参与酪氨酸蛋白激酶(jak)/信号传导子和转录激活子3(stat3)传导途径的负反馈调节,可能参与akt的磷酸化,进而调控肿瘤的发生.根据socs3蛋白的生物学特性和akt信号通路的激活途径,综述了socs3在akt信号通路中的调控作用,以期针对socs3靶向akt信号通路进行抗肿瘤研究,为肿瘤的治疗提供一种新的思路.
Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells
Yun-Hee Rhee, Soo-Jin Jeong, Hyo-Jeong Lee, Hyo-Jung Lee, Wonil Koh, Ji Jung, Sun-Hee Kim, Kim Sung-Hoon
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-28
Abstract: Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control.These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.Ergosterol Peroxide (EP), 5α, 8α-epidioxy-22E-ergosta-6, 22-dien-3β-ol, is found in plants [1], lichens [2] and mushrooms such as Ganoderma lucidum [3], Sporothrix schenckii [4] and Cordyceps sinensis [5]. Despite various biological effects of EP such as immunosuppressive [6-8], anti-viral [9], anti-inflammatory [10] and anti-tumor [5,10] activities, the underlying molecular mechanisms for anti-cancer activity of EP still remain unclear.STAT proteins originally discovered as latent cytoplasmic transcription factors [11] are involved in a variety of cellular processes such as cell proliferation, differentiation and apoptosis [12,13]. Of the STAT proteins, STAT3 is often constitutively activated in many human cancer cells including multiple myeloma, leukemia,
汉黄芩素增敏TNF促肿瘤细胞凋亡的实验研究
An experimental study of wogonin enhancing TNF antitumor activity though JNK pathway
 [PDF]

杨岚,王霞,王琼,孙虹
- , 2015,
Abstract: 摘要:目的 研究JNK通路在汉黄芩素增敏TNF促进肺癌干细胞凋亡的作用机制。方法 采用汉黄芩素和TNF单独或联合用药,LDH检测细胞凋亡,免疫蛋白印记(Western Bloting,WB)检测JNK磷酸化水平和凋亡蛋白的表达。结果 汉黄芩素显著增强TNF诱导的抗肿瘤作用,并且这个作用通过促进TNF诱导的JNK 通路的磷酸化来实现。同时伴随潜在的TNF诱导的caspase 8活化,引起凋亡的启动。凋亡抑制因子zVAD-fmk和JNK通路抑制因子SP600125均可以扭转这种凋亡。更为重要的是,汉黄芩素对于正常的支气管上皮细胞则不会出现增敏TNF诱导细胞凋亡的作用。结论 汉黄芩素可能通过促进JNK通路磷酸化增敏TNF抗肺癌作用。
Icaritin Shows Potent Anti-Leukemia Activity on Chronic Myeloid Leukemia In Vitro and In Vivo by Regulating MAPK/ERK/JNK and JAK2/STAT3 /AKT Signalings  [PDF]
Jian feng Zhu, Zi jian Li, Guang sen Zhang, Kun Meng, Wen yong Kuang, Jin Li, Xin fu Zhou, Rui juan Li, Hong ling Peng, Chong wen Dai, Jian Kai Shen, Fan jie Gong, Yun xiao Xu, Su fang Liu
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023720
Abstract: Purpose To explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms. Method CML cells were incubated with various concentration of Icaritin for 48 hours, the cell proliferation was analyzed by MTT and the apoptosis was assessed with Annexin V and Hoechst 33258 staining. Cell hemoglobinization was determined. Western blotting was used to evaluate the expressions of MAPK/ERK/JNK signal pathway and Jak-2/Phorpho-Stat3/Phorsph-Akt network-related protein. NOD-SCID nude mice were applied to demonstrate the anti-leukemia effect of Icaritin in vivo. Results Icaritin potently inhibited proliferation of K562 cells (IC50 was 8 μM) and primary CML cells (IC50 was 13.4 μM for CML-CP and 18 μM for CML-BC), induced CML cells apoptosis and promoted the erythroid differentiation of K562 cells with time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis. In mouse leukemia model, Icaritin could prolong lifespan of NOD-SCID nude mice inoculated with K562 cells as effective as Imatinib without suppression of bone marrow. Icaritin could up-regulate phospho-JNK or phospho-C-Jun and down-regulate phospho-ERK, phospho-P-38, Jak-2, phospho-Stat3 and phospho-Akt expression with dose- or time-dependent manner. Icaritin had no influence both on c-Abl and phospho-c-Abl protein expression and mRNA levels of Bcr/Abl. Conclusion Icaritin from Chinese herb medicine may be a potential anti-CML agent with low adverse effect. The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML.
STAT3 Oligonucleotide Inhibits Tumor Angiogenesis in Preclinical Models of Squamous Cell Carcinoma  [PDF]
Jonah D. Klein, Daisuke Sano, Malabika Sen, Jeffrey N. Myers, Jennifer R. Grandis, Seungwon Kim
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0081819
Abstract: Purpose Signal transducer and activator of transcription 3 (STAT3) has shown to play a critical role in head and neck squamous cell carcinoma (HNSCC) and we have recently completed clinical trials of STAT3 decoy oligonucleotide in patients with recurrent or metastatic HNSCC. However, there is limited understanding of the role of STAT3 in modulating other aspects of tumorigenesis such as angiogenesis. In this study, we aimed to examine the effects of STAT3 decoy oligonucleotide on tumor angiogenesis. Experimental Design A STAT3 decoy oligonucleotide and small interfering RNA (siRNA) were used to inhibit STAT3 in endothelial cells in vitro and in vivo. The biochemical effects of STAT3 inhibition were examined in conjunction with the consequences on proliferation, migration, apoptotic staining, and tubule formation. Additionally, we assessed the effects of STAT3 inhibition on tumor angiogenesis using murine xenograft models. Results STAT3 decoy oligonucleotide decreased proliferation, induces apoptosis, decreased migration, and decreased tubule formation of endothelial cells in vitro. The STAT3 decoy oligonucleotide also inhibited tumor angiogenesis in murine tumor xenografts. Lastly, our data suggest that the antiangiogenic effects of STAT3 decoy oligonucleotide were mediatedthrough the inhibition of both STAT3 and STAT1. Conclusions The STAT3 decoy oligonucleotidewas found to be an effective antiangiogenic agent, which is likely to contribute to the overall antitumor effects of this agent in solid tumors.Taken together with the previously demonstrated antitumor activity of this agent, STAT3 decoy oligonucleotide represents a promising single agent approach to targeting both the tumor and vascular compartments in various malignancies.
Oxidative stress in NSC-741909-induced apoptosis of cancer cells
Xiaoli Wei, Wei Guo, Shuhong Wu, Li Wang, Peng Huang, Jinsong Liu, Bingliang Fang
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-37
Abstract: The generation of ROS was measured by using the cell-permeable nonfluorescent compound H2DCF-DA and flow cytometry analysis. Cell viability was determined by sulforhodamine B assay. Western blot analysis, immunofluorescent staining and flow cytometry assays were used to determine apoptosis and molecular changes induced by NSC-741909.Treatment with NSC-741909 induced robust ROS generation and marked MAPK phosphatase-1 and -7 clustering in NSC-741909-sensitive, but not resistant cell lines, in a dose- and time-dependent manner. The generation of ROS was detectable as early as 30 min and ROS levels were as high as 6- to 8-fold above basal levels after treatment. Moreover, the NSC-741909-induced ROS generation could be blocked by pretreatment with antioxidants, such as nordihydroguaiaretic acid, aesculetin, baicalein, and caffeic acid, which in turn, inhibited the NSC-741909-induced JNK activation and apoptosis.Our results demonstrate that the increased ROS production was associated with NSC-741909-induced antitumor activity and that ROS generation and subsequent JNK activation is one of the primary mechanisms of NSC-741909-mediated antitumor cell activity.We recently identified a small molecule (oncrasin-1) through cell-based synthetic lethality screening that can effectively kill several lung cancer cell lines harboring mutant K-Ras genes [1]. Subsequent analyses of oncrasin-1 analogues led us to identify several active compounds with similar chemical structures. NSC-741909 is one of the oncrasin-1 analogues that was highly active against several cell lines derived from lung, colon, breast, ovarian, and kidney cancers when tested in NCI-60 cancer cell lines by the Developmental Therapeutics Program at the National Cancer Institute. Using a reverse-phase protein microarray assay, we determined molecular changes in 77 protein biomarkers in an oncrasin-sensitive lung cancer cell line after treatment with NSC-741909 [2]. These results showed that treatment with NSC-741909
Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3  [cached]
Fang-Ming Gu,Quan-Lin Li,Qiang Gao,Jia-Hao Jiang
World Journal of Gastroenterology , 2011, DOI: 10.3748/wjg.v17.i34.3922
Abstract: AIM: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC). METHODS: Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC model. RESULTS: Sorafenib decreased STAT3 phosphorylation at the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phospha-tase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib significantly inhibited STAT3 activity, reducing tumor growth and metastasis. CONCLUSION: Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.
Luteolin Induces Carcinoma Cell Apoptosis through Binding Hsp90 to Suppress Constitutive Activation of STAT3  [PDF]
Jin Fu, Dan Chen, Bo Zhao, Zhihui Zhao, Jiahong Zhou, Yimiao Xu, Yinqiang Xin, Chang Liu, Lan Luo, Zhimin Yin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049194
Abstract: Background Abnormal activity of STAT3 is associated with a number of human malignancies. Hsp90 plays a central role in stabilizing newly synthesized proteins and participates in maintaining the functional competency of a number of signaling transducers involved in cell growth, survival and oncogenesis, such as STAT3. Hsp90 interacts with STAT3 and stabilizes Tyr-phosphorylated STAT3. It has been reported that luteolin possesses anticancer activity through degradation of Tyr705-phosphorylated STAT3. Methodology/Principal Findings We found that overexpression of Hsp90 inhibited luteolin-induced degradation of Tyr705-phosphorylated STAT3 and luteolin also reduced the levels of some other Hsp90 interacting proteins. Results from co-immunoprecipitation and immunoblot analysis demonstrated that luteolin prevented the association between Hsp90 and STAT3 and induced both Tyr705- and Ser727-phosphorylated STAT3 degradation through proteasome-dependent pathway. The molecular modeling analysis with CHARMm–Discovery Studio 2.1(DS 2.1) indicated that luteolin could bind to the ATP-binding pocket of Hsp90. SPR technology-based binding assay confirmed the association between luteolin and Hsp90. ATP-sepharose binding assay displayed that luteolin inhibited Hsp90-ATP binding. Conclusions/Significance Luteolin promoted the degradation of Tyr705- and Ser727-phosphorylated STAT3 through interacting with Hsp90 and induced apoptosis of cancer cells. This study indicated that luteolin may act as a potent HSP90 inhibitor in antitumor strategies.
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