scholarly journals P01.14 Excessive biological ageing of circulating neutrophils in cancer promotes tumor progression

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A15.1-A15
Author(s):  
CA Reichel ◽  
L Mittmann ◽  
J Schaubächer ◽  
R Hennel ◽  
G Zuchtriegel ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Cell Line ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Biological Ageing ◽  
Functional Changes ◽  
Age Related

BackgroundBeyond their well-established role in host defense, neutrophils are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, ageing of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their anti-infectious properties. The role of neutrophil ageing in cancer is still unknown.Material and MethodsEmploying syngeneic mouse models of head and neck squamous cell carcinoma (cell line SCC VII) and breast cancer (cell line 4T1), cytokine expression (by multiplex ELISA), neutrophil trafficking (by multi-channel in vivo microscopy and flow cytometry), and neutrophil function (in vitro assays) were analyzed.ResultsHere, we show that signals released during early tumor growth promote excessive biological ageing of circulating neutrophils as indicated by age-related changes in their molecular repertoire. These events facilitate the accumulation of these highly reactive immune cells in malignant lesions and endow them with potent pro-tumorigenic functions. In particular, excessively aged neutrophils release neutrophil elastase which, in turn, stimulates the proliferation of cancer cells. Counteracting accelerated biological ageing of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.ConclusionsOur experimental data uncover a potent self-sustaining mechanism of malignant tumors in fostering pro-tumorigenic phenotypic and functional changes in circulating neutrophils, thus supporting tumor progression. Interference with this aberrant process might provide a novel, already pharmacologically targetable strategy for cancer therapy. This study was supported by Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich (SFB) 914.Disclosure InformationC.A. Reichel: None. L. Mittmann: None. J. Schaubächer: None. R. Hennel: None. G. Zuchtriegel: None. M. Canis: None. O. Gires: None. F. Krombach: None. L. Holdt: None. S. Brandau: None. T. Vogl: None. K. Lauber: None. B. Uhl: None.

scholarly journals Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression

2021 ◽  
Vol 9 (12) ◽  
pp. e003495
Author(s):  
Laura A Mittmann ◽  
Florian Haring ◽  
Johanna B Schaubächer ◽  
Roman Hennel ◽  
Bojan Smiljanov ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Ex Vivo ◽  
Biological Aging ◽  
Malignant Neoplasms ◽  
Chronological Aging ◽  
Functional Changes

BackgroundBeyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure.MethodsEmploying advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various ex vivo/in vitro assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer.ResultsHere, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.ConclusionsOur data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.

scholarly journals lncRNA CASC19 Contributes to Radioresistance of Nasopharyngeal Carcinoma by Promoting Autophagy via AMPK-mTOR Pathway

2021 ◽  
Vol 22 (3) ◽  
pp. 1407
Author(s):  
Hongxia Liu ◽  
Wang Zheng ◽  
Qianping Chen ◽  
Yuchuan Zhou ◽  
Yan Pan ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cell Line ◽  
Malignant Tumors ◽  
Underlying Mechanism ◽  
Mtor Pathway ◽  
Rna Seq ◽  
Cellular Autophagy ◽  
First Time

Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors and is majorly treated by radiotherapy. However, radiation resistance remains a serious obstacle to the successful treatment of NPC. The aim of this study was to discover the underlying mechanism of radioresistance and to elucidate novel genes that may play important roles in the regulation of NPC radiosensitivity. By using RNA-seq analysis of NPC cell line CNE2 and its radioresistant cell line CNE2R, lncRNA CASC19 was screened out as a candidate radioresistance marker. Both in vitro and in vivo data demonstrated that a high expression level of CASC19 was positively correlated with the radioresistance of NPC, and the radiosensitivity of NPC cells was considerably enhanced by knockdown of CASC19. The incidence of autophagy was enhanced in CNE2R in comparison with CNE2 and another NPC cell line HONE1, and silencing autophagy with LC3 siRNA (siLC3) sensitized NPC cells to irradiation. Furthermore, CASC19 siRNA (siCASC19) suppressed cellular autophagy by inhibiting the AMPK/mTOR pathway and promoted apoptosis through the PARP1 pathway. Our results revealed for the first time that lncRNA CASC19 contributed to the radioresistance of NPC by regulating autophagy. In significance, CASC19 might be a potential molecular biomarker and a new therapeutic target in NPC.

Therapeutic Efficacy and Cure Of Sensitive and T315I Pan-Resistant Human Ph+ Leukemia In Mice Using a TCR-Like Antibody To WT1/HLA-A0201 Alone, Or In Combination With Tyrosine Kinase Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 855-855
Author(s):  
Leonid Dubrovsky ◽  
Elliott Brea ◽  
Dmitry Pankov ◽  
Nicholas Veomett ◽  
Tao Dao ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Tyrosine Kinase ◽  
Tumor Growth ◽  
Cell Line ◽  
Wilms Tumor ◽  
High Dose ◽  
Human Leukemia ◽  
Rt Pcr

Abstract Acute and chronic leukemias, including CD34+ CML stem cells, overexpress the Wilms tumor gene 1 (WT1) protein, making WT1 an attractive therapeutic target. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201, allowing it to target an undruggable, widely expressed, intracellular oncogene product. BV173 is an HLA-A0201+, human Ph+ ALL cell line that expresses WT1, and tagged by our lab with luciferase. We engineered a tyrosine kinase inhibitor (TKI) resistant BV173-R cell line by transducing BV173 with the resistant T315I Bcr-Abl plasmid. Antibody-dependent cellular cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. Tumor growth in vivo was assessed in NOD/SCID gamma (NSG) mice with bioluminescence imaging (BLI). RT-PCR was used to evaluate minimal residual disease in mice with negative BLI signal at the end of therapy. Imatinib, dasatinib, and ponatinib were used at up to maximally tolerated doses, given IP once daily. ESKM was administered at 100 µg twice weekly IP. ESKM mediated ADCC against both BV173 and BV173-R cell lines in vitro. In a BV173 engrafted human leukemia xenograft model, ESKM was more potent than imatinib, with median tumor growth reduction of 78% vs 52%. Combination of imatinib and ESKM therapy resulted in a 94% reduction in leukemic growth. High dose dasatinib (40 mg/kg daily) was more potent than ESKM, but discontinuation of therapy due to dasatinib toxicity resulted in relapse. Combination with ESKM therapy with dasatinib resulted in cure in 75% of mice, confirmed by bone marrow RT-PCR three weeks after termination of therapy. For mice cytoreduced with dasatinib followed by consolidation therapy with ESKM, delayed relapse was observed, but no cures. ESKM was highly superior to imatinib and dasatinib against the T315I BV173-R leukemia in vivo. Cures were not achieved with combination therapy of ESKM and either first or second generation TKIs against resistant T315I leukemia. Ponatinib at 10 mg/kg had higher efficacy than ESKM alone against BV173-R, but mice treated with combination of ESKM and ponatinib had superior tumor reduction. CONCLUSION: ESKM is an effective therapeutic antibody for sensitive and T315I Ph+ ALL. Resistant T315I Ph+ leukemic growth is inhibited more effectively by ESKM therapy compared to imatinib and dasatinib, and combination therapy with ESKM is superior to ponatinib. Supported by the Leukemia and Lymphoma Society, NIH R01CA55349, P01 23766 and T32CA62948-18. Disclosures: Yan: Eureka Therapeutics: Employment. Liu:Eureka Therapeutics: Employment, Equity Ownership.

scholarly journals Combinations of TLR Ligands: A Promising Approach in Cancer Immunotherapy

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Saskia Stier ◽  
Claudia Maletzki ◽  
Ulrike Klier ◽  
Michael Linnebacher
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
Immune Cells ◽  
Human Lymphocytes ◽  
Growth Control ◽  
Poly I:C ◽  
The Impact

Toll-like receptors (TLRs), a family of pattern recognition receptors recognizing molecules expressed by pathogens, are typically expressed by immune cells. However, several recent studies revealed functional TLR expression also on tumor cells. Their expression is a two-sided coin for tumor cells. Not only tumor-promoting effects of TLR ligands are described but also direct oncopathic and immunostimulatory effects. To clarify TLRs’ role in colorectal cancer (CRC), we tested the impact of the TLR ligands LPS, Poly I:C, R848, and Taxol on primary human CRC cell lines (HROC40, HROC60, and HROC69)in vitroandin vivo(CT26). Taxol, not only a potent tumor-apoptosis-inducing, but also TLR4-activating chemotherapeutic compound, inhibited growth and viability of all cell lines, whereas the remaining TLR ligands had only marginal effects (R848 > LPS > Poly I:C). Combinations of the substances here did not improve the results, whereas antitumoral effects were dramatically boosted when human lymphocytes were added. Here, combining the TLR ligands often diminished antitumoral effects.In vivo, best tumor growth control was achieved by the combination of Taxol and R848. However, when combined with LPS, Taxol accelerated tumor growth. These data generally prove the potential of TLR ligands to control tumor growth and activate immune cells, but they also demonstrate the importance of choosing the right combinations.

scholarly journals Targeted Inhibition of PI3K α/δ Is Synergistic with BCL-2 Blockade in Genetically Defined Subtypes of DLBCL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 39-39
Author(s):  
Kamil Bojarczuk ◽  
Kirsty Wienand ◽  
Jeremy A. Ryan ◽  
Linfeng Chen ◽  
Mariana Villalobos-Ortiz ◽  
...  
Keyword(s):  
Tumor Growth ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Research Funding ◽  
Single Agent ◽  
Research Report ◽  
Genetic Bases

Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease that is transcriptionally classified into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. A subset of both GCB- and ABC-DLBCLs are dependent on B-cell receptor (BCR) signaling. Previously, we defined distinct BCR/PI3K-mediated survival pathways and subtype-specific apoptotic mechanisms in BCR-dependent DLBCLs (Cancer Cell 2013 23:826). In BCR-dependent DLBCLs with low baseline NF-κB activity (GCB tumors), targeted inhibition or genetic depletion of BCR/PI3K pathway components induced expression of the pro-apoptotic HRK protein. In BCR-dependent DLBCLs with high NF-κB activity (ABC tumors), BCR/PI3K inhibition decreased expression of the anti-apoptotic NF-κB target gene, BFL1. Our recent analyses revealed genetic bases for perturbed BCR/PI3K signaling and defined poor prognosis DLBCL subsets with discrete BCR/PI3K/TLR pathway alterations (Nat Med 2018 24:679). Cluster 3 DLBCLs (largely GCB tumors) exhibited frequent PTEN deletions/mutations and GNA13 mutations. Cluster 5 DLBCLs (largely ABC tumors) had frequent MYD88L265P and CD79B mutations that often occurred together. These DLBCL subtypes also had different genetic mechanisms for deregulated BCL2 expression - BCL2 translocations in Cluster 3 and focal (18q21.33) or arm level (18q) BCL2 copy number gains in Cluster 5. These observations prompted us to explore the activity of PI3K inhibitors and BCL2 blockade in genetically defined DLBCLs. We utilized a panel of 10 well characterized DLBCL cell line models, a subset of which exhibited hallmark genetic features of Cluster 3 and Cluster 5. We first evaluated the cytotoxic activity of isoform-specific, dual PI3Kα/δ and pan-PI3K inhibitors. In in vitro assays, the PI3Kα/δ inhibitor, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. We next assessed the transcriptional abundance of BCL2 family genes in the DLBCLs following copanlisib treatment. In BCR-dependent GCB-DLBCLs, there was highly significant induction of the pro-apoptotic HRK. In BCR-dependent ABC-DLBCLs, we observed significant down-regulation of the anti-apoptotic BFL1 protein and another NF-κB target gene, BCLxL (the anti-apoptotic partner of HRK). We then used BH3 profiling, to identify dependencies on certain BCL2 family members and to correlate these data with sensitivity to copanlisib. BCLxL dependency significantly correlated with sensitivity to copanlisib. Importantly, the BCLxL dependency was highest in DLBCL cell lines that exhibited either transcriptional up-regulation of HRK or down-regulation of BCLxL following copanlisib treatment. In all our DLBCL cell lines, PI3Kα/δ inhibition did not alter BCL2 expression. Given the genetic bases for BCL-2 deregulation in a subset of these DLBCLs, we next assessed the activity of the single-agent BCL2 inhibitor, venetoclax, in in vitro cytotoxicity assays. A subset of DLBCL cell lines was partially or completely resistant to venetoclax despite having genetic alterations of BCL2. We postulated that BCR-dependent DLBCLs with structural alterations of BCL2 might exhibit increased sensitivity to combined inhibition of PI3Kα/δ and BCL2 and assessed the cytotoxic activity of copanlisib (0-250 nM) and venetoclax (0-250 nM) in the DLBCL cell line panel. The copanlisib/venetoclax combination was highly synergistic (Chou-Talalay CI<1) in BCR-dependent DLBCL cell lines with genetic bases of BCL2 deregulation. We next assessed copanlisib and venetoclax activity in an in vivo xenograft model using a DLBCL cell line with PTENdel and BCL2 translocation (LY1). In this model, single-agent copanlisib did not delay tumor growth or improve survival. Single-agent venetoclax delayed tumor growth and improved median survival (27 vs 51 days, p<0.0001). Most notably, we found that the combination of copanlisib and venetoclax delayed tumor growth significantly longer than single-agent venetoclax (p<0.0001). Additionally, the combined therapy significantly increased survival in comparison with venetoclax alone (median survival 51 days vs not reached, p<0.0013). Taken together, these results provide in vitro and in vivo pre-clinical evidence for the rational combination of PI3Kα/δ and BCL2 blockade and set the stage for clinical evaluation of copanlisib/venetoclax therapy in patients with genetically defined relapsed/refractory DLBCL. Disclosures Letai: AbbVie: Consultancy, Other: Lab research report; Flash Therapeutics: Equity Ownership; Novartis: Consultancy, Other: Lab research report; Vivid Biosciences: Equity Ownership; AstraZeneca: Consultancy, Other: Lab research report. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.

scholarly journals Combination Therapy of a Host Defense-Like Lytic Peptide and Continuous Low-Dose Doxorubicin Inhibits Tumor Growth in a Syngeneic Immunocompetent Murine Fibrosarcoma (BFS-1) Model

2020 ◽  
Author(s):  
Jan Philip Suppelna ◽  
Kamran Harati ◽  
Andrea Rittig ◽  
Ingo Stricker ◽  
Markus Lehnhardt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Cell Line ◽  
Host Defense ◽  
Low Dose ◽  
Sarcoma Cell ◽  
Fibrosarcoma Cell ◽  
Murine Fibrosarcoma

Abstract Background: The concept of a multimodality therapy in the treatment of soft tissue sarcomas (STS) has been discussed with controversy. Surgical resection with clear margins and radiation therapy remain gold standard in STS therapy. It is still questionable whether a systemic therapy with chemotherapeutics has a positive impact on the overall survival rate especially in early stages of disease, because the therapeutic effect in the treatment of STS is limited by its toxicities and its low responding rates. Treatment options are rare. As a result the search for combination therapies by using low dose approaches is of high importance. Recent studies showed the therapeutic efficiency of a designer host defense-like lytic D,L- amino acid peptide [D]-K 3 H 3 L 9 . Therefore we tested a combination of this peptide with Doxorubicin on two different sarcoma cell lines in vitro and also in a syngeneic immunocompetent murine fibrosarcoma mouse model. Methods: In vitro the human synovial sarcoma cell line SW 982 and the murine fibrosarcoma cell line BFS-1 were exposed to the oncolytic peptide [D]-K 3 H 3 L 9 , to the Anthracycline Doxorubicin and to both agents simultaneously. In vivo the murine fibrosarcoma cell line BFS-1 was injected subcutaneously into the syngeneic mice. When the tumors engrafted the oncolytic designer peptide [D]-K 3 H 3 L 9 , Doxorubicin or a combination of both was administered thrice a week for a three weeks’ follow-up. Results: The combination treatment approach using an oncolytic designer host defense peptide and Doxorubicin inhibited the in vitro sarcoma cell proliferation significantly. The single therapies, either with local intratumoral application of [D]-K 3 H 3 L 9 or with intraperitoneal application of Doxorubicin in the syngeneic mouse model, inhibited at least the tumor progression. The combination of both substances revealed a significant inhibition of tumor growth and weight. Conclusion: The in vivo low dose combination schedule inhibited the tumor growth significantly. Histological analyses of the tumor sections revealed an antiproliferative and antiangiogenic effect. So, these results demonstrate the effectiveness of combined low-dose application forms with designer host defense-like lytic peptides and chemotherapeutics.

Increasing Wnt3a Signaling in Myeloma Cells Inhibits the Osteolytic Phenotype and Tumor Growth In Vivo through Regulation of the RANKL/OPG Axis in Osteoblasts and Indirectly Regulates Osteoclastogenesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3506-3506
Author(s):  
Ya-Wei Qiang ◽  
Nathan Brown ◽  
Yu Chen ◽  
Shmuel Yaccoby ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Wnt Signaling ◽  
Cell Line ◽  
Osteoclast Formation ◽  
C2c12 Cells ◽  
Myeloma Cells ◽  
Protein Levels ◽  
Canonical Wnt

Abstract We have demonstrated that canonical and non-canonical Wnt signaling occurs in myeloma cells (Qiang et al., 2005) and overexpression of Wnt3a in myeloma cells inhibits the osteolytic phenotype and also tumor growth in vivo (Qiang et al Blood, Abstract #3420, 2006). To further investigate the mechanisms that contribute to this process we have expanded our in vivo data by showing that while H929 cells stably expressing Wnt3a (H929/W3a) leads to reduced tumor growth in the in-vivo SCID-hu bone graft model compared with H929 vector alone transfected control cells (H929/EV), there was no significant difference in the subcutaneous growth of the two cell lines in SCID mice. Taken together these data suggests that alteration of the human bone marrow microenvironment is central to Wnt-mediated reduction in tumor growth in bone. We next employed an in-vitro co-culture model in which the mouse osteoprogenitor cell line, C2C12, and human osteoblast cell line, Saos-2 were co-cultured with either H929/Wnt3 or H929/EV cells. QPCR analysis demonstrated that osteoprotegerin (OPG) mRNA expression (relative OPG mRNA to GAPDH) in C2C12 cells co-cultured with H929/W3a was significantly elevated compared with H929/EV (mean±SD: 14.34±0.97 vs 8.43±0.16; P<0.001). ELISA analysis showed that OPG protein levels in the cell culture supernatant were also significantly higher (71.02 ± 6.178 vs 0 pg/ml; P<0.001). Similar results in OPG mRNA and protein levels were observed in Saos-2 cells co-cultured with H929/W3a relative to H929/EV. Furthermore, treatment of C2C12 cells with recombinant Wnt3a protein induced both OPG mRNA (48.1 ±1.2 vs 1.0±0.5; P<0.001) and protein levels (1767.03 ± 44.8 vs 1.11 ± 0.03 p< 0.0001) compared with vehicle alone. These results suggest that forced expression of a canonical Wnt ligand by MM cells might promote OPG transcription in osteoblast progenitors in-vivo. To further confirm the role of Wnt signaling in regulation of OPG and RANKL transcription, we produced C2C12 cells that stably express Dkk1. These clones showed a significant inhibition of Wnt3a induced OPG mRNA (22.2± 2.3 vs 1.7±0.35; p<0.001) and protein (73.3 ± 18.0 vs. 0 pg/ml; p<0.01) compared with vector control. In contrast, RANKL mRNA (5.1±0.9 vs 1.0± 0.5, p<0.01) and protein (9.3±3.8 vs. 0 pg/ml; p<0.01) were increased in Dkk1 expressing clones compared with control. Moreover, supernatant from C2C12 clones stably expressing a DN-beta-catenin (DNBC/C2C12) contained a significantly higher level of RANKL (17.3± 3.5 pg/ml vs. 0±0; P<0.001) and a dramatically lower level of OPG protein (0±0 vs. 431.186 pg/ml; P<0.001) compared with control. Finally, the numbers of multinuclear TRAP-positive osteoclasts were significantly more abundant in culture containing supernatant from DNBC/C2C12 than that from vector control, while Wnt3a exposure had no effect on osteoclast formation in-vitro. Taken together, these data suggest that Wnt ligand-mediated inhibition of myeloma cell growth, and inhibition of osteolytic lesions, in-vivo may result from upregulation of OPG and loss of RANKL in osteoblast progenitors, which subsequently diminishes osteoclast formation. Results of these studies provide new insights into mechanism by which Wnts may serve as an important indirect regulator of myeloma growth and osteoclast formation, and as such, targeting Wnt signaling may be an new therapeutic strategy for controlling myeloma growth and associated bone disease.

scholarly journals Mouse plasmacytoma growth in vivo: enhancement by interleukin 6 (IL-6) and inhibition by antibodies directed against IL-6 or its receptor.

1990 ◽  
Vol 172 (3) ◽  
pp. 997-1000 ◽  
Author(s):  
A Vink ◽  
P Coulie ◽  
G Warnier ◽  
J C Renauld ◽  
M Stevens ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Growth ◽  
Cell Line ◽  
Interleukin 6 ◽  
Essential Role ◽  
Expression Vector ◽  
Tumor Challenge ◽  
Present Evidence

Murine plasmacytomas show a striking dependence on interleukin 6 (IL-6) for their growth in vitro. Here, we present evidence suggesting that IL-6 also plays an essential role in the in vivo development of these tumors. This conclusion is based on the finding that the tumorigenicity of an IL-6-dependent plasmacytoma cell line was increased approximately 100-fold on transfection with an IL-6 expression vector, whereas it was inhibited in animals treated with monoclonal antibodies capable of blocking the binding of IL-6 to its receptor. Injection of these antibodies 1 d before tumor challenge protected greater than 50% of the mice and retarded tumor growth in all animals. Tumors arising in antibody-treated mice retained their IL-6 dependence in vitro, suggesting that the level of protection could be improved if stronger IL-6 antagonists were available.

scholarly journals Huzhangoside A Suppresses Tumor Growth through Inhibition of Pyruvate Dehydrogenase Kinase Activity

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 712 ◽  
Author(s):  
Choong-Hwan Kwak ◽  
Jung-Hee Lee ◽  
Eun-Yeong Kim ◽  
Chang Woo Han ◽  
Keuk-Jun Kim ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pyruvate Dehydrogenase ◽  
Malignant Tumors ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
In Vitro Assays ◽  
In Vivo Models

Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity.

Sign in / Sign up

Export Citation Format

Share Document