scholarly journals In VitroandIn VivoAntitumor Effects of n-Butanol Extracts ofPterocephalus hookerion Hep3B Cancer Cell

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Chenxu Guo ◽  
Yingchun Wu ◽  
Yuanzhang Zhu ◽  
Yanchun Wang ◽  
Lili Tian ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cancer Cell ◽  
Akt Phosphorylation ◽  
Transmission Electron ◽  
Hep3b Cells ◽  
Strong Antitumor Activity ◽  
Induced Apoptosis ◽  
Hepatoma Carcinoma Cell

Pterocephalus hookeriis a widely applied Tibetan medicinal prescription for treatment of diseases such as flu, rheumatoid arthritis, and enteritis in China. It has been reported thatPterocephalus hookerihas anti-inflammatory and analgesic actions. However, the antitumor activity ofPterocephalus hookeriremains unknown. In the present study, we demonstrate that n-butanol extracts ofPterocephalus hookeri(YSC-ZDC) has a strong antitumor activity against hepatoma carcinoma cellin vitroandin vivo. YSC-ZDC inhibited proliferation of all cancer cell lines and significantly inhibited Hep3B cells proliferation in a dose- and time-dependant manner. Transmission electron microscopy, hoechst 33258 staining, and flow cytometry analysis revealed that YSC-ZDC induced apoptosis in Hep3B cells. YSC-ZDC treatment dramatically inhibited PDK1 and Akt phosphorylation in Hep3B cells. Moreover, YSC-ZDC increased Bax expression and inhibited Bcl-2 expression. In addition, YSC-ZDC inhibited growth hepatoma xenograftsin vivowith no effect on body weight and spleen index. Consistent with resultsin vitro, YSC-ZDC increased Bax expression and inhibited Bcl-2 expression in tumor tissue. Taken together, this study shows YSC-ZDC with an antitumor activity bothin vitroandin vivo. Its mechanism underlying is related to blocking of the Akt pathway and regulation of Bcl-2 family proteins expression.

scholarly journals Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1838
Author(s):  
Naglaa M. Ahmed ◽  
Mahmoud M. Youns ◽  
Moustafa K. Soltan ◽  
Ahmed M. Said
Keyword(s):  
Molecular Modeling ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

scholarly journals Elevated pressure enhanced TRAIL-induced apoptosis in hepatocellular carcinoma cells via ERK1/2-inactivation

2015 ◽  
Vol 20 (4) ◽  
Author(s):  
Eunyoung Hong ◽  
Eunil Lee ◽  
Joonhee Kim ◽  
Daeho Kwon ◽  
Yongchul Lim
Keyword(s):  
Specific Inhibitor ◽  
Underlying Mechanism ◽  
Elevated Pressure ◽  
Mitochondrial Pathway ◽  
Carcinoma Cells ◽  
Intrinsic Resistance ◽  
Hep3b Cells ◽  
Induced Apoptosis

AbstractThe high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs.

Antitumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13170-13170
Author(s):  
M. P. Morelli ◽  
T. Cascone ◽  
T. Troiani ◽  
C. Tuccillo ◽  
R. Bianco ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Antitumor Activity ◽  
Cancer Cell ◽  
Combination Treatment ◽  
Growth Delay ◽  
Tumor Growth Delay

13170 Background: The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 (ZACTIMA™) is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the antitumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells. Methods: The antitumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway. Results: In vitro, the combination of ZD6474 and cetuximab produced synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In vivo, 4 weeks of treatment with ZD6474 (75 mg/kg p.o., days 1–5 each week) or cetuximab (1 mg i.p., days 2 and 5 each week) produced a tumor growth delay of 21–28 days (P < 0.001) in nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) cancer xenografts compared with untreated controls. Combination treatment with ZD6474 and cetuximab for 4 weeks resulted in a more marked tumor growth delay of 120–140 days compared with controls, and this was significantly greater than with either single agent therapy (P < 0.001). Following combination treatment, 3/10 A549 xenograft-bearing mice and 4/10 GEO xenograft-bearing mice had no histologic evidence of tumor at the end of the experiment. Immunohistochemical analysis of tumor samples obtained from mice treated with the two drugs in combination demonstrated a cooperative inhibition of cancer cell proliferation and an almost complete suppression of tumor angiogenesis. Conclusions: This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR-2 signaling as cancer therapy. [Table: see text]

scholarly journals Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Yun Huang ◽  
Chen Liu ◽  
Wu-Cha Zeng ◽  
Guo-Yan Xu ◽  
Jian-Min Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Inhibitory Effect ◽  
Cycle Arrest ◽  
Novel Drugs ◽  
Epithelial Marker ◽  
Hep3b Cells ◽  
Induced Apoptosis

Abstract The overall survival rate of patients with hepatocellular carcinoma (HCC) has remained unchanged over the last several decades. Therefore, novel drugs and therapies are required for HCC treatment. Isoliquiritigenin (ISL), a natural flavonoid predominantly isolated from the traditional Chinese medicine Glycyrrhizae Radix (Licorice), has a high anticancer potential and broad application value in various cancers. Here, we aimed to investigate the anticancer role of ISL in the HCC cell line Hep3B. Functional analysis revealed that ISL inhibited the proliferation of Hep3B cells by causing G1/S cell cycle arrest in vitro. Meanwhile, the inhibitory effect of ISL on proliferation was also observed in vivo. Further analysis revealed that ISL could suppress the migration and metastasis of Hep3B cells in vitro and in vivo. Mechanistic analysis revealed that ISL inhibited cyclin D1 and up-regulated the proteins P21, P27 that negatively regulate the cell cycle. Furthermore, ISL induced apoptosis while inhibiting cell cycle transition. In addition, phosphatidylinositol 3′-kinase/protein kinase B (PI3K/AKT) signal pathway was suppressed by ISL treatment, and the epithelial marker E-cadherin was up-regulated when the mesenchymal markers Vimentin and N-cadherin were down-regulated. In brief, our findings suggest that ISL could be a promising agent for preventing HCC tumorigenesis and metastasis.

scholarly journals Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4053-4062 ◽  
Author(s):  
Teru Hideshima ◽  
Laurence Catley ◽  
Hiroshi Yasui ◽  
Kenji Ishitsuka ◽  
Noopur Raje ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mononuclear Cells ◽  
Antitumor Agents ◽  
Mek Inhibitor ◽  
Peripheral Blood Mononuclear ◽  
Akt Phosphorylation ◽  
Human Multiple Myeloma ◽  
Induced Apoptosis

Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline phosphorylation of Akt in multiple myeloma (MM) cells is completely inhibited by perifosine [octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate] in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation. Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant to conventional therapeutic agents. Perifosine does not induce cytotoxicity in peripheral blood mononuclear cells. Neither exogenous interleukin-6 (IL-6) nor insulinlike growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity. Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells. Perifosine triggers c-Jun N-terminal kinase (JNK) activation, followed by caspase-8/9 and poly (ADP)-ribose polymerase cleavage. Inhibition of JNK abrogates perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in perifosine-induced apoptosis. Interestingly, phosphorylation of extracellular signal–related kinase (ERK) is increased by perifosine; conversely, MEK inhibitor synergistically enhances Perifosine-induced cytotoxicity in MM cells. Furthermore, perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity. Finally, perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with down-regulation of Akt phosphorylation in tumor cells. Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM.

Perifosine, an Oral Bioactive Novel Akt Inhibitor, Induces In Vitro and In Vivo Antitumor Activity in Waldenstrom Macroglobulinemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2488-2488 ◽  
Author(s):  
Xavier Leleu ◽  
Xiaoying Jia ◽  
Anne-Sophie Moreau ◽  
Evdoxia Hatjiharisi ◽  
Hai Ngo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Antitumor Activity ◽  
Dna Synthesis ◽  
Cell Lines ◽  
Akt Pathway ◽  
Low Grade ◽  
Akt Inhibitor ◽  
Induced Apoptosis

Abstract Background: Waldenstrom’s Macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma with limited options of therapy. The PI3k/Akt pathway is a critical regulator of cell survival. Our previous studies using proteomic analysis have demonstrated upregulation of members of the PI3k/Akt pathway in WM. We examined whether the new Akt inhibitor perifosine (NSC 639966; Keryx, NY) induces cytotoxicity in WM. Methods: WM cell lines (BCWM1 and WSU-WM) and IgM secreting low-grade lymphoma cell lines (MEC1, RL) were used. Primary CD19+ malignant cells were obtained from patients after informed consent. Inhibition of proliferation was measured using the MTT assay; DNA synthesis was measured using the thymidine uptake assay and apoptosis using Apo2.7 flow cytometry. Bone marrow stromal cells (BMSC) confer growth and resistance to conventional treatments. We therefore, tested the effect of perifosine on WM cells co-cultured with BMSC. Immunoblotting for signaling pathways was performed at different time (30 minutes to 16 hrs) and doses of therapy. In vivo activity of perifosine was assessed using a SCID-irradiated model with subcutaneous tumors in which perifosine was administered by oral gavage daily (35 mg/kg/day). A two-sided t-test was used to determine statistical differences. Results: Perifosine inhibited phosphorylation of Akt in a dose- and time- dependent fashion, as well as downstream GSK3a/b and ribosomal phospho-S6. Perifosine inhibited Akt activity as confirmed by Akt kinase assay. Perifosine induced significant cytotoxicity and inhibition of DNA synthesis with an IC50 of 5-20uM in all cell lines tested. Similar effects were observed in primary CD19+ patient WM cells. Perifosine induced apoptosis in WM cells as demonstrated by flow cytometry. The mechanism of apoptosis induced by perifosine was through activation of SAPK/JNK pathway, followed by caspase-8, -9 and PARP cleavage. The JNK inhibitor SP600125 abrogated perifosine-induced apoptosis. The growth inhibitory effects of perifosine were significant even in the presence of BMSC, IL-6 and IGF-1, which induce resistance to conventional therapies. Importantly, perifosine did not induce cytotoxicity in healthy donor peripheral blood mononuclear cells or in hematopietic stem cells in a methylcellulose colony forming cell assay, indicating lack of toxicity on normal cells. Interestingly, MAPK members such as MEK/ERK were activated by perifosine. The MEK inhibitor U0126 significantly enhanced perifosine-induced cytotoxicity in WM cells, indicating that this combination may be synergistic in vivo. Finally, perifosine induced significant reduction in WM tumor growth in vivo, as compared to control cohort treated with vehicle only at week 6 (p=0.05). Conclusion: Perifosine has significant antitumor activity in WM both in vitro and in vivo. These results provide the framework for clinical evaluation of perifosine in WM. Supported in part by the Leukemia and Lymphoma Society, the Lymphoma Research Foundation and an American Society of Hematology Scholar Award. * XL and XJ are co-first authors.

Antitumor activity of a polysaccharide from longan seed on lung cancer cell line A549 in vitro and in vivo

Tumor Biology ◽  
2014 ◽  
Vol 35 (7) ◽  
pp. 7259-7266 ◽  
Author(s):  
Hongmin Wang ◽  
Xiaohong Zhang ◽  
Yuexia Li ◽  
Ruiying Chen ◽  
Songyun Ouyang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Lung Cancer Cell ◽  
Longan Seed

scholarly journals A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xuan Deng ◽  
Fanyang Kong ◽  
Si Li ◽  
Haoqin Jiang ◽  
Liu Dong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
In Vivo Models ◽  
Akt Phosphorylation ◽  
New Class ◽  
H3k27me3 Level ◽  
Tumor Tissues ◽  
Signaling Axis ◽  
Induced Apoptosis

AbstractLong noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in colorectal cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin-resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL’s role in conferring resistance to oxaliplatin-induced apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance.

scholarly journals Bortezomib potentiates antitumor activity of Mitoxantrone through dampening Wnt/β-catenin signaling pathway in prostate cancel cells

2021 ◽  
Author(s):  
Ying Zhang ◽  
Qiuzi Liu ◽  
Wei Wei ◽  
Guoan Zhang ◽  
Siyuan Yan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Signaling Pathway ◽  
Target Genes ◽  
Proliferation Assay ◽  
Prostate Cancer Cells ◽  
Anticancer Effects ◽  
Induced Apoptosis

Abstract Background Bortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown.Methods Anticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of β-catenin and its target genes were characterized by western blot and Real-time PCR.Results BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/β-catenin signaling pathway compared to monotherapy.Conclusions This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/β-catenin signaling pathway in prostate cancer cells.

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