Effects of the multikinase inhibitor regorafenib in neuroblastoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10553-10553
Author(s):  
Peter E. Zage ◽  
Divya Subramonian ◽  
Qianxing Mo ◽  
Shixia Huang
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Viability ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Therapeutic Potential ◽  
Neuroblastoma Cells ◽  
Dependent Manner ◽  
Western Blots

10553 Background: Neuroblastoma (NB) is the most common extracranial solid pediatric tumor, and children with high-risk NB have poor survival rates and need novel treatment strategies. Regorafenib, a multi-receptor tyrosine kinase (RTK) inhibitor approved for treating adult solid tumors such as advanced metastatic colorectal cancer and gastrointestinal stromal tumors, inhibits many RTKs, including PDGFR-β, VEGFR1-3, RET, c-Kit and FGFR family members. Based on the potential roles for these targets in neuroblastoma pathogenesis, we explored the therapeutic potential of Regorafenib alone and in combination with 13-cis-retinoic acid against neuroblastoma cells. Methods: We treated NB cell lines with increasing concentrations of Regorafenib and measured cell viability using MTT assays. We further measured the occupied percent confluence over time using continuous live cell imaging. We performed Western blots for caspase cleavage to measure apoptosis and flow cytometry to determine cell cycle expression. We performed Reverse Phase Protein Array (RPPA) analysis of neuroblastoma cells before and after treatment with regorafenib combined with 13- cis-retinoic acid. Results: IC50values for the tested cell lines ranged between 2.5mcM and 12.5mcM after 72 hours of exposure to Regorafenib, and decreased viability was due to a combination of apoptosis and cell cycle arrest. RPPA analysis identified alterations in multiple proteins and pathways after Regorafenib with retinoic acid treatment, including the PI3K/Akt/mTOR and Jak/Stat pathways. Phosphorylation of Erk1/2, S6, Akt, and c-Jun were decreased, while protein expression of GATA3 was increased in a dose-dependent manner. Conclusions: Regorafenib treatment results in reduced neuroblastoma cell viability and increased apoptosis via effects on several signaling pathways. Effects on intracellular signaling pathways associated with responses to the combination of regorafenib plus retinoic acid represent opportunities to develop novel combination therapies, representing potential new therapeutic strategies for children with neuroblastoma.

scholarly journals Resveratrol Induces Cell Cycle Arrest and Apoptosis in Malignant NK Cells Via JAK2/STAT3 Pathway Inhibition

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1343-1343 ◽  
Author(s):  
Ly Quoc Trung ◽  
Luis Jorge Espinoza ◽  
Akiyoshi Takami ◽  
Akiyo Yoshida ◽  
Shinji Nakao
Keyword(s):  
Cell Cycle ◽  
Nk Cells ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Stat3 Pathway ◽  
Cycle Arrest

Abstract Abstract 1343 Natural killer (NK)-cell malignancies, particularly aggressive NK-cell leukemias/lymphomas, have poor prognoses. Although recent regimens that include L-asparaginase substantially improve outcomes, novel therapeutic approaches are needed to improve clinical responses. Recent reports have shown that the signal transducer and activator of transcription 3 (STAT3) pathway is critical for proliferation and survival of malignant NK cells. Resveratrol is a naturally-occurring polyphenol that has been extensively studied for its anti-inflammatory, cardioprotective, and anti-cancer activities. In this study, we investigated the potential anti-tumor activities of resveratrol against the NK cell lines KHYG-1, NKL, NK-92, and NK-YS. Resveratrol significantly suppressed cell proliferation in a dose- and time-dependent manner in these four cell lines. Flow cytometry analysis with annexin V/propidium iodide staining showed a variable but consistent induction of apoptosis in the four cell lines treated with resveratrol for 48 hours, ranging from 57.1±6.9% of apoptosis in the L-asparaginase resistant cell line KHYG-1 to 53.4±9.7%, 28.8±3.3%, and 51.7±6.7% in NKL, NK-92, and NK-YS cells respectively (Fig. 1a). Notably, the anti-tumor activity of resveratrol against NK cell lines was p53 independent as demonstrated by equal efficacy of resveratrol against NK cell lines pretreated with the p53 inhibitor Pifithrin-α. Immunoblot analysis to study intracellular signaling in resveratrol-treated cells showed suppression of constitutively active STAT3 in all four cell lines 24 hours after treatment. Remarkably, resveratrol inhibited JAK2 phosphorylation, but had no effect on other known upstream mediators of STAT3 activation such as PTEN and Tyk2 (Fig. 1b). Resveratrol induced robust G1 cell cycle arrest and down-regulation of two anti-apoptotic proteins, Mcl-1 and survivin, both of which are downstream effectors of the STAT-3 pathway. Furthermore, resveratrol enhanced the pro-apoptotic and anti-proliferative activities of L-asparaginase against NKL and NK-92 cells by 32% and 126% respectively. These data indicate that resveratrol possesses a potent anti-tumor effect via inactivation of the STAT3 pathway in malignant NK cells. These mechanistic findings suggest that resveratrol may have therapeutic potential against NK cell malignancies. Our finding that resveratrol is a bonafide JAK2 inhibitor extends its therapeutic potential to other diseases with deregulated JAK2 signaling. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol through the Modulation of EGFR and CSC Signaling Pathways

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 681 ◽  
Author(s):  
Phuong Doan ◽  
Aliyu Musa ◽  
Akshaya Murugesan ◽  
Vili Sipilä ◽  
Nuno R. Candeias ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Glioblastoma Multiforme ◽  
Cell Cycle Arrest ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Cell Population ◽  
Significant Role ◽  
Dependent Manner ◽  
Cycle Arrest

Cancer stem cells (CSCs), a small subpopulation of cells existing in the tumor microenvironment promoting cell proliferation and growth. Targeting the stemness of the CSC population would offer a vital therapeutic opportunity. 3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), a small synthetic phenol compound, is proposed to play a significant role in controlling the CSC proliferation and survival. We assessed the potential therapeutic effects of THTMP on glioblastoma multiforme (GBM) and its underlying mechanism in various signaling pathways. To fully comprehend the effect of THTMP on the CSCs, CD133+ GBM stem cell (GSC) and CD133- GBM Non-stem cancer cells (NSCC) population from LN229 and SNB19 cell lines was used. Cell cycle arrest, apoptosis assay and transcriptome analysis were performed for individual cell population. THTMP strongly inhibited NSCC and in a subtle way for GSC in a time-dependent manner and inhibit the resistance variants better than that of temozolomide (TMZ). THTMP arrest the CSC cell population at both G1/S and G2/M phase and induce ROS-mediated apoptosis. Gene expression profiling characterize THTMP as an inhibitor of the p53 signaling pathway causing DNA damage and cell cycle arrest in CSC population. We show that the THTMP majorly affects the EGFR and CSC signaling pathways. Specifically, modulation of key genes involved in Wnt, Notch and Hedgehog, revealed the significant role of THTMP in disrupting the CSCs’ stemness and functions. Moreover, THTMP inhibited cell growth, proliferation and metastasis of multiple mesenchymal patient-tissue derived GBM-cell lines. THTMP arrests GBM stem cell cycle through the modulation of EGFR and CSC signaling pathways.

scholarly journals Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors In Vitro: Antitumoral Effects

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 345
Author(s):  
Xi-Feng Jin ◽  
Gerald Spöttl ◽  
Julian Maurer ◽  
Svenja Nölting ◽  
Christoph Josef Auernhammer
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cell Lines ◽  
Neuroendocrine Tumors ◽  
Density Lipoprotein ◽  
Time Dependent ◽  
Dependent Manner ◽  
Antitumor Properties

Background and aims: Inhibition of Wnt/β-catenin signaling by specific inhibitors is currently being investigated as an antitumoral strategy for various cancers. The role of Wnt/β-catenin signaling in neuroendocrine tumors still needs to be further investigated. Methods: This study investigated the antitumor activity of the porcupine (PORCN) inhibitor WNT974 and the β-catenin inhibitor PRI-724 in human neuroendocrine tumor (NET) cell lines BON1, QGP-1, and NCI-H727 in vitro. NET cells were treated with WNT974, PRI-724, or small interfering ribonucleic acids against β-catenin, and subsequent analyses included cell viability assays, flow cytometric cell cycle analysis, caspase3/7 assays and Western blot analysis. Results: Treatment of NET cells with WNT974 significantly reduced NET cell viability in a dose- and time-dependent manner by inducing NET cell cycle arrest at the G1 and G2/M phases without inducing apoptosis. WNT974 primarily blocked Wnt/β-catenin signaling by the dose- and time-dependent downregulation of low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation and non-phosphorylated β-catenin and total β-catenin, as well as the genes targeting the latter (c-Myc and cyclinD1). Furthermore, the WNT974-induced reduction of NET cell viability occurred through the inhibition of GSK-3-dependent or independent signaling (including pAKT/mTOR, pEGFR and pIGFR signaling). Similarly, treatment of NET cells with the β-catenin inhibitor PRI-724 caused significant growth inhibition, while the knockdown of β-catenin expression by siRNA reduced NET tumor cell viability of BON1 cells but not of NCI-H727 cells. Conclusions: The PORCN inhibitor WNT974 possesses antitumor properties in NET cell lines by inhibiting Wnt and related signaling. In addition, the β-catenin inhibitor PRI-724 possesses antitumor properties in NET cell lines. Future studies are needed to determine the role of Wnt/β-catenin signaling in NET as a potential therapeutic target.

scholarly journals Rapamycin inhibits proliferation and induces autophagy in human neuroblastoma cells

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Xiaokun Lin ◽  
Lei Han ◽  
Jialei Weng ◽  
Kelai Wang ◽  
Tongke Chen
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Morphological Changes ◽  
Mammalian Target Of Rapamycin ◽  
Neuroblastoma Cells ◽  
Beclin 1 ◽  
Cell Counting ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Expression Levels

Objective To investigate the effect of Rapamycin on proliferation and autophagy in human neuroblastoma (NB) cell lines and to elucidate the possible mechanism. Methods NB cells were treated with different concentrations of Rapamycin. Cell counting kit-8 (CCK-8) was used to measure proliferation, and flow cytometry (FCM) was used to analyze the cell cycle. EM was used to observe cell morphological changes. Western blotting (WB) was performed to detect the expression of Beclin-1, LC3-I/II, P62, mammalian target of Rapamycin (mTOR), and p-mTOR. Results Rapamycin inhibited the spread of NB cells in a dose- and time-dependent manner and arrested the cell cycle at the G0/G1 phase. EM showed autophagosomes in NB cells treated with Rapamycin. The WB results showed that the expression levels of Beclin-1 and LC3-II/LC3-I were significantly elevated in NB cells treated with Rapamycin, while the expression levels of P62, mTOR, and p-mTOR proteins were significantly reduced compared with the control cells (P<0.05). Conclusion Rapamycin inhibits cell proliferation and induces autophagy in human NB cell lines. The mechanism may be related to suppression of the mTOR signaling pathway.

scholarly journals Capsaicin and Dihydrocapsaicin Extracted from Capsicum chinenses Decrease Cell Viability of Neuroblastoma SH-SY5Y Cells In Vitro

2021 ◽  
Author(s):  
Joseph Ayariga ◽  
Daniel A. Abugri ◽  
Gerald D. Griffin
Keyword(s):  
Molecular Docking ◽  
Cell Viability ◽  
Therapeutic Potential ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
High Dose ◽  
Solid Cancer ◽  
Dependent Manner ◽  
In Vivo Models

Neuroblastoma is an extra-cranial solid cancer that primarily affects children. Aggressive neuroblastoma tumors typically demonstrate resistance to conventional chemotherapeutic and radiotherapeutic regimens. Interestingly, the use of dietary supplements in the control of cancers has gained ascendance in recent scientific investigations. Capsaicin and dihydrocapsaicin are bioactive components of Capsicum chinenses fruit. Qutenza (a high-dose capsaicin patch) is used in the management of neuropathic pain from postherpetic neuralgia and HIV-associated neuropathy. Research on the potency of capsaicin as an anticancer agent has been demonstrated on several cancer cell lines and in in vivo models. The possibility of conventional cancer therapies having long-term developmental and other side effects on pediatric patients invokes the need to search for other less toxic agents against neuroblastoma. In this study, we tested if Capsicum chinenses fruit extract has therapeutic potential against neuroblastoma. To carry out this study, capsaicin and dihydrocapsaicin extract were made from Capsicum chinenses red fruits via hexane extraction method. Then, a range of concentrations (1pg/mL&ndash;100 mg/mL) of the extract was administered to cultured SH-SY5Y neuroblastoma cells and their viabilities assessed. The potency of capsaicin in destroying neuroblastoma cells indicated that it might act via multiple routes, hence we screen for possible receptors in and on neuroblastoma cells that might interact with capsaicin using molecular docking techniques. Our findings showed that capsaicin and dihydrocapsaicin extracted from Capsicum chinenses reduced neuroblastoma cell viability in a concentration-dependent manner with an IC50 of 69.75 &micro;g/mL. Our in-silico analysis determined that capsaicin might potentially bind to other receptors on the surface of neuroblastoma cells. We demonstrated a stronger binding affinity of capsaicin to human D4 Dopamine receptor (DRD4) than to the known vanilloid receptor TRPV1 using molecular docking. In conclusion, these results illustrated that Capsicum chinenses extract containing capsaicin and dihydrocapsaicin is effective in reducing viability of neuroblastoma cells in vitro and may serve as a naturally derived treatment source for this pediatric cancer, secondly, capsaicin may have multiple targets, and its strong binding to human D4 Dopamine receptors may point to different pathways by which capsaicin exerts its cancer killing effects.

2-Chlorodeoxyadenosine (2-CDA) and Dexamethasone Induce Apoptosis in Multiple Myeloma (MM) Via Different Mechanisms.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4792-4792
Author(s):  
Bolin Liu ◽  
Zeying Fang ◽  
Jian Ma ◽  
Thomas E. Dillon ◽  
Tim E. Byers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Inhibition ◽  
Cell Lines ◽  
B Lymphocyte ◽  
Therapeutic Potential ◽  
Growth Control ◽  
Cross Resistance ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Ic50 Values

Abstract Although 2-CDA has been active on B-lymphocyte derived malignancies, its potential for myeloma growth control has not been fully investigated. In the present study on a pair of MM cell lines, dexamethasone-sensitive (MM1.S) and dexamethasone-resistant (MM1.R), we sought to determine whether 2-CDA can effectively induce apoptosis and growth inhibition in both cell lines and whether there is cross resistance between 2-CDA and dexamethasone in MM1.R cells. Cell proliferation assay (MTS) releaved that 2-CDA significantly inhibited both MM1.S and MM1.R cell growth in a dose dependent manner, with the minimum (10%) and maximum (100%) inhibition concentration of 12.5 nM/L and 500 nM/L for the MM1.S, and 25 nM/L and 500 nM/L for the MM1.R cells, respectively. The IC50 values of 2-CDA in the MM1.S and MM1.R cells were 48 nM/L and 60 nM/L, respectively. No cross resistance was observed between 2-CDA and dexamethasone in the MM1.R cells. On the molecular level, dexamethasone induced PARP and caspase-9 cleavage, and increased the level of p27kip1 only in the MM1.S cells. 2-CDA treatment in both cell lines resulted in DNA fragmentation as well as strong PARP and caspase-9 cleavage, but no significant changes in the levels of P-Akt, P-MARK, p27kip1, E2F1, and cyclin D1, indicating that 2-CDA induces growth inhibition and cell death in MM cell lines likely through mitochondria-dependent apoptotic mechanism. Cell cycle analyses by flow cytometry showed that dexamethasone (5μM/L) treatment increased sub-G1 (apoptosis) cells to 8.1% only in the MM1.S cells, while the majority (87%) of cells were arrested in the G1 phase of cell cycle in 24 hours. In contrast, 2-CDA (0.5μM/L for 24 hours) strongly induced apoptosis in both cell lines (sub-G1 population increased to 19.6% and 22.1% for the MM1.S and MM1.R cells, respectively) without changing their cell cycle profiles. These data suggest that dexamethasone and 2-CDA induce apoptosis in myeloma cells via different mechanisms, which would provide a theoretical basis for combination therapy for MM with these two agents. Furthermore, our results also show that 2-CDA alone is capable of inducing apoptosis in the MM1.R cells, suggesting that 2-CDA may have therapeutic potential for MM patients with a dexamethasone-resistant phenotype.

Mechanisms of Pseudolaric Acid B-Induced Apoptosis in Bel-7402 Cell Lines

2006 ◽  
Vol 34 (05) ◽  
pp. 887-899 ◽  
Author(s):  
Wan-Ying Wu ◽  
Hong-Zhu Guo ◽  
Gui-Qin Qu ◽  
Jian Han ◽  
De-An Guo
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Dna Fragmentation ◽  
Cell Lines ◽  
Caspase 3 ◽  
Human Tumor ◽  
Dependent Manner ◽  
Pseudolaric Acid B ◽  
M Phase ◽  
Induced Apoptosis

Previous studies have shown that pseudolaric acid B (PB) would cause apoptosis in human tumor cell lines. However, the mechanisms of PB induced apoptosis are still unclear. In the present study, the mechanisms of PB induced apoptosis in the human hepatocellular carcinoma Bel-7402 cell line were investigated by measuring cell viability, rate of apoptosis, cell cycle, detecting DNA fragmentation, and measuring caspase-3 activation. The results indicated that PB inhibited Bel-7402 cell viability and induced cell death by causing DNA fragmentation, up regulating the early and late apoptotic rates, activating caspase-3 protein, and detaining the cell cycle in the G2/M phases. Additionally, PB-induced apoptosis was a dose- and time-dependent manner. These observations suggest that PB-induced apoptosis occurs through a caspase-dependent pathway and detains the cell cycle in the G2/M phase.

scholarly journals Effects of Vanadyl Complexes with Acetylacetonate Derivatives on Non-Tumor and Tumor Cell Lines

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5534
Author(s):  
Valentina Boscaro ◽  
Alessandro Barge ◽  
Annamaria Deagostino ◽  
Elena Ghibaudi ◽  
Enzo Laurenti ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinases ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Biological Effects ◽  
Dependent Manner ◽  
Inhibition Of Proliferation ◽  
Mitogen Activated Protein Kinases ◽  
Vanadyl Complexes ◽  
Mitogen Activated Protein

Vanadium has a good therapeutic potential, as several biological effects, but few side effects, have been demonstrated. Evidence suggests that vanadium compounds could represent a new class of non-platinum, metal antitumor agents. In the present study, we aimed to characterize the antiproliferative activities of fluorescent vanadyl complexes with acetylacetonate derivates bearing asymmetric substitutions on the β-dicarbonyl moiety on different cell lines. The effects of fluorescent vanadyl complexes on proliferation and cell cycle modulation in different cell lines were detected by ATP content using the CellTiter-Glo Luminescent Assay and flow cytometry, respectively. Western blotting was performed to assess the modulation of mitogen-activated protein kinases (MAPKs) and relevant proteins. Confocal microscopy revealed that complexes were mainly localized in the cytoplasm, with a diffuse distribution, as in podocyte or a more aggregate conformation, as in the other cell lines. The effects of complexes on cell cycle were studied by cytofluorimetry and Western blot analysis, suggesting that the inhibition of proliferation could be correlated with a block in the G2/M phase of cell cycle and an increase in cdc2 phosphorylation. Complexes modulated mitogen-activated protein kinases (MAPKs) activation in a cell-dependent manner, but MAPK modulation can only partly explain the antiproliferative activity of these complexes. All together our results demonstrate that antiproliferative effects mediated by these compounds are cell type-dependent and involve the cdc2 and MAPKs pathway.

scholarly journals Ricolinostat (ACY-1215), a Selective HDAC6 Inhibitor, Alone and in Combination with Bendamustine Is Effective in Preclinical Studies in Lymphoma Cell Lines

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2772-2772
Author(s):  
Maria Cosenza ◽  
Monica Civallero ◽  
Steven N Quayle ◽  
Stefano Sacchi ◽  
Samantha Pozzi
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Lines ◽  
Drug Combination ◽  
Histone Deacetylase Inhibitors ◽  
Epigenetic Therapy ◽  
Ros Generation ◽  
Preclinical Studies ◽  
Dependent Manner

Abstract Background. Histone deacetylase inhibitors (HDACi) have emerged as a new class of anticancer agents, targeting the biological processes including cell cycle and apoptosis. The discovery of isoform selective compounds may offer a therapeutic advantage by minimizing toxicity. Ricolinostat (ACY-1215) inhibits HDAC6, resulting in tubulin hyperacetylation. Previous studies have investigated the synergistic effects of the combination of HDACis and alkylating agents offering new therapeutic strategies. The aim of this in vitro study was to investigate the activity of ricolinostat alone and in combination with bendamustine in a panel of non-Hodgkin's lymphoma (NHL) cell lines. Methods. Ricolinostat was kindly provided by Acetylon Pharmaceuticals (Boston). NHL cell lines (WSU-NHL, RL, Granta-519, Jeko-1, Hut-78 and Karpas-299) were treated with ricolinostat and bendamustine alone and in combination. The interaction between the drugs was evaluated by the Chou-Talalay method and cell viability and clonogenicity were also evaluated. Apoptosis, ROS generation, Bcl-2 protein expression, cell cycle progression and tubulin expression were determined by flow cytometry. The effects of ricolinostat alone and in combination on caspases, PI3K/Akt, ER stress and UPR pathways were assessed by immunoblotting. Results. Ricolinostat was able to affect the cell viability in a dose dependent manner, with IC50 values ranging from 1.51 to 8.65 μM. Ricolinostat with bendamustine synergistically induced anti-proliferative and pro-apoptotic effects in lymphoma cells, even in the presence of the bone marrow microenvironment. Combination treatment decreased the percentage of viable peripheral blood mononuclear cells (PBMCs) from patients with lymphoma but had minimal or no cytotoxic effect on PBMCs from healthy donors. Clonogenic assay revealed that the drug combination significantly inhibited the colony formation compared with the drugs alone. Drug combination reduced the proportion of cells in the G0/G1 and S phases and caused an increase of "sub-G0/G1" peak with a decrease of cyclin D1 and cyclin E and an increase of p21 and p27 proteins. The synergistic effect was accompanied by increased reactive oxygen species (ROS) generation, which is linked to a decrease of thioredoxin-1 (Trx1) expression, activation of caspase -8, -9, and -3, the cleavage of PARP and modulation of the Bcl-2 protein family. Apoptosis was associated with increased hallmarks of ER stress and activation of UPR sensors and was mediated by dephosphorylation of the AKT. In addition, the exposure of ricolinostat induced the acetylation level of α-tubulin, the extent of which was not further modified by bendamustine. The direct cytotoxicity of ricolinostat/bendamustine may be mediated by an effect on microtubule stabilization. Finally, ricolinostat alone induced a significant down-regulation of IL-10 that was especially evident in WSU-NHL with a fold decrease of 6.6 compared to control. The drug combination affected IL-10 production in all three cell lines with a fold decrease of 5.77 in WSU-NL; 11.5 in Hut-78; and 10.9 in Jeko-1 cells compared with ricolinostat alone. Conclusion. These preclinical studies suggest that bendamustine in combination with epigenetic therapy, such as ricolinostat, may be a promising treatment regime for managing lymphomas. Disclosures Quayle: Acetylon Pharmaceuticals: Employment, Equity Ownership.

A Cytotoxic Natural Product from Patrinia villosa Juss

2019 ◽  
Vol 19 (11) ◽  
pp. 1399-1404 ◽  
Author(s):  
Yangcheng Liu ◽  
Wei Liu ◽  
Changlan Chen ◽  
Zheng Xiang ◽  
Hongwei Liu
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Silica Gel ◽  
Column Chromatography ◽  
Bioactive Compound ◽  
Antitumor Agent ◽  
2D Nmr ◽  
Preparative Hplc ◽  
Dependent Manner ◽  
2D Nmr Spectra

Background and Purpose:: Patrinia villosa Juss is an important Chinese herbal medicine widely used for thousands of years, but few reports on the ingredients of the herb have been presented. In this study, we aim to isolate the bioactive compound from the plant. Material and Methods:: The air-dried leaves of P. villosa (15kg) were extracted three times with 70% EtOH under reflux. The condensed extract was suspended in H2O and partitioned with light petroleum, dichloromethane and n-BuOH. The dichloromethane portion was then subjected to normal-phase silica gel column chromatography, ODS silica gel column chromatography and semi-preparative HPLC to yield compound 1. Cytotoxicities of 1 were assayed on HepG2, A549 and A2780 cell lines. The mechanism of apoptosis and cell cycle on A549 was confirmed subsequently. Results: A new impecylone (Impecylone A) was isolated from the leaves of Patrinia villosa Juss, and its structures were established using 1D, 2D-NMR spectra and HR-ESI-MS. Impecylone A could selectivity inhibit HepG2 and A549 cell lines. The compound could induce apoptosis of A549 and arrest the cell cycle at G2/M phase in a dose-dependent manner. Conclusion: Impecylone A is a novel compound from Patrinia villosa Juss and could be a potential antitumor agent especially in the cell lines of A549.

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