scholarly journals Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation

2021 ◽  
Author(s):  
Gaofeng Fan ◽  
Xiaobao Yang ◽  
Biao Jiang ◽  
Yong Cang ◽  
Haixia Liu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Dependent Manner ◽  
Salvage Pathway ◽  
Prognosis Factor ◽  
Killing Effect ◽  
Multiple Tumor ◽  
Nad Synthesis ◽  
Hematological Tumor ◽  
Rate Limiting

The rate-limiting enzyme of salvage pathway for NAD+ synthesis, NAMPT, is aberrantly overexpressed in a variety of tumor cells and is a poor prognosis factor for patient survival. NAMPT plays a major role in tumor cell proliferation, acting concurrently as an NAD+ synthase and unexpectedly, an extracellular ligand for several tumor-promoting signaling pathways. While previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously disrupt NAMPT enzyme activity and ligand capabilities. Here, we report the development of two highly selective NAMPT-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent NAMPT degradation in a cereblon-dependent manner in multiple tumor cell lines. Notably, both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a better strategy for targeting proteins like NAMPT with dual tumor-promoting functions, which are not easily achieved by conventional enzymatic inhibitors.

scholarly journals Biochemical and Anti-Triple Negative Metastatic Breast Tumor Cell Properties of Psammaplins

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 442 ◽  
Author(s):  
Yu-Dong Zhou ◽  
Jun Li ◽  
Lin Du ◽  
Fakhri Mahdi ◽  
Thuy Le ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Breast Tumor ◽  
Triple Negative ◽  
Hdac Inhibitors ◽  
Metastatic Breast ◽  
Dependent Manner ◽  
Breast Tumor Cells ◽  
Metastatic Breast Tumor

Breast tumors reprogram their cellular metabolism, nutrient uptake, and utilization-associated biochemical processes. These processes become further transformed as genetically predisposed metastatic breast tumor cells colonize specific organs. Breast tumor cells often metastasize to the brain, bone, lung and liver. Massagué and colleagues isolated organotropic subclones and established organ-specific gene signatures associated with lung-, bone-, and brain-specific metastatic triple-negative breast cancer (TNBC) MDA-MB-231 cells. Using these genetically characterized metastatic subclones specific to lung (LM4175), bone (BoM1833), and brain (BrM-2a), we evaluated marine natural products for the ability to differentially suppress metastatic breast cancer cells in a target organ-dependent manner. Psammaplin-based histone deacetylase (HDAC) inhibitors were found to differentially inhibit HDAC activity, induce activation of hypoxia-inducible factor-1 (HIF-1), and disrupt organotropic metastatic TNBC subclone growth. Further, psammaplins distinctly suppressed the outgrowth of BoM1833 tumor spheroids in 3D-culture systems. Similar results were observed with the prototypical HDAC inhibitor trichostatin A (TSA). These organotropic tumor cell-based studies suggest the potential application of HDAC inhibitors that may yield new directions for anti-metastatic breast tumor research and drug discovery.

Synergy of nanodiamond-doxorubicin conjugates and PD-L1 blockade effectively turns tumor associated macrophages against tumor cells

2021 ◽  
Author(s):  
Huazhen Xu ◽  
Tongfei Li ◽  
Chao Wang ◽  
Yan Ma ◽  
Yan Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Lung Cancer Cells ◽  
Dependent Manner ◽  
Tumor Associated Macrophages ◽  
M1 Type

Abstract Background: Tumor-associated macrophages (TAM) are the most abundant stromal cells in the tumor microenvironment. Turning the TAM against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAM into the anti-tumor M1 phenotype. Results: Nano-DOX were first shown to stimulate the tumor cells and the TAM to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAM. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAM both by blocking Nano-DOX-induced PD-L1 in the TAM and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAM with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner. Conclusions: PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAM to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAM, achieves enhanced activation of TAM-mediated anti-tumor response.

scholarly journals 242 Pharmacologic tumor PD-L1 depletion with chlorambucil treats ovarian cancer and melanomas in a tumor PD-L1-dependent manner and renders αPD-L1-resistant tumors αPD-L1-sensitive

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A261-A261
Author(s):  
Haiyan Bai ◽  
Álvaro Padrón ◽  
Yilun Deng ◽  
Anand Kornepati ◽  
Srikanth Polusani ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Nk Cell ◽  
San Antonio ◽  
Cell Generation ◽  
List Type ◽  
Dependent Manner ◽  
Cell Content

BackgroundProgrammed cell death ligand-1 (PD-L1) overexpression in tumor cells inhibits T cells activity and delivers pathologic intracellular signals that can reduce cancer treatment responses in pre-clinicalmodels.1 2MethodsTo reduce tumor intracellular PD-L1-mediated pathology, we performed a drug screen that identified chlorambucil as a tumor cell PD-L1 depletion drug.ResultsChlorambucil depletes basal tumor PD-L1 expression through the ubiquitination proteasome pathway. In the tumor microenvironment, high chlorambucil doses treated orthotopic B16 melanoma and ID8agg ovarian cancer. Chlorambucil treatment efficacy was lost or reduced in PD-L1lo ID8agg and PD-L1KO B16 tumors, corroborated with in vitro data. These data suggest that chlorambucil anti-tumor activity of CAMB requires tumor PD-L1 expression, confirmed in PD-L1KO host challenge with CTRL tumor, which chlorambucil treated effectively. Chlorambucil rendered αPD-L1 resistant CTRL ID8agg and PD-L1lo B16 tumors αPD-L1 sensitive, preliminarily possibly due to tumor STING activation, and associated with enhanced tumor NK cell infiltration and central memory T cell generation. Chlorambucil also phenocopied genetic PD-L1KO by reducing tumor cell mTORC1 signals and stem cell content,3 suggesting additional treatment potential.ConclusionsChlorambucil could be a useful strategy to reprogram tumor PD-L1 signals and boost immune-based therapies especially for anti-PD-L1-resistant tumors.ReferencesClark CA et al. Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res 2016;76:6964–6974.Juneja VR et al. PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 2017;214:895–904.Gupta HB et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 2016;1:2095–9907.Ethics ApprovalWe received approval from the UT Health San Antonio Institutional Animal Care and Use Committee (IACUC) for each procedure that used mice. We conducted each experiment per the standards required by the UT Health San Antonio Department of Laboratory Animal Resources.

scholarly journals Innate extracellular vesicles from melanoma patients suppress β-catenin in tumor cells by miRNA-34a

2019 ◽  
Vol 2 (2) ◽  
pp. e201800205 ◽  
Author(s):  
Jung-Hyun Lee ◽  
Jochen Dindorf ◽  
Martin Eberhardt ◽  
Xin Lai ◽  
Christian Ostalecki ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Clinical Stage ◽  
Tumor Resection ◽  
Cell Activity ◽  
Tumor Development ◽  
Dependent Manner ◽  
Primary Surgery ◽  
Melanoma Patients

Upon tumor development, new extracellular vesicles appear in circulation. Our knowledge of their relative abundance, function, and overall impact on cancer development is still preliminary. Here, we demonstrate that plasma extracellular vesicles (pEVs) of non-tumor origin are persistently increased in untreated and post-excision melanoma patients, exhibiting strong suppressive effects on the proliferation of tumor cells. Plasma vesicle numbers, miRNAs, and protein levels were elevated two- to tenfold and detected many years after tumor resection. The vesicles revealed individual and clinical stage-specific miRNA profiles as well as active ADAM10. However, whereas pEV from patients preventing tumor relapse down-regulated β-catenin and blocked tumor cell proliferation in an miR-34a–dependent manner, pEV from metastatic patients lost this ability and stimulated β-catenin–mediated transcription. Cancer-induced pEV may constitute an innate immune mechanism suppressing tumor cell activity including that of residual cancer cells present after primary surgery.

scholarly journals Precision glycocalyx editing as a strategy for cancer immunotherapy

2016 ◽  
Vol 113 (37) ◽  
pp. 10304-10309 ◽  
Author(s):  
Han Xiao ◽  
Elliot C. Woods ◽  
Petar Vukojicic ◽  
Carolyn R. Bertozzi
Keyword(s):  
Tumor Cell ◽  
Natural Killer ◽  
Tumor Cells ◽  
Immune Modulation ◽  
Nk Cell ◽  
Immune Therapy ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Trastuzumab Resistance ◽  
Enhance Tumor Cell

Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody–sialidase conjugates that enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag. The antibody–sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by natural killer (NK) cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and enhanced binding to the NK-activating receptor natural killer group 2D (NKG2D). Sialidase conjugation to trastuzumab enhanced ADCC against tumor cells expressing moderate levels of HER2, suggesting a therapeutic strategy for cancer patients with lower HER2 levels or inherent trastuzumab resistance. Precision glycocalyx editing with antibody–enzyme conjugates is therefore a promising avenue for cancer immune therapy.

Effects of Berberine on Arylamine N-Acetyltransferase Activity in Human Colon Tumor Cells

1999 ◽  
Vol 27 (02) ◽  
pp. 265-275 ◽  
Author(s):  
J.G. Lin ◽  
J.G. Chung ◽  
L.T. Wu ◽  
G.W. Chen ◽  
H.L. Chang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Line ◽  
Tumor Cells ◽  
Human Colon ◽  
Colon Tumor ◽  
Dependent Manner ◽  
Aminobenzoic Acid ◽  
Intact Cells ◽  
Viable Cells ◽  
Colon Tumor Cell

Berberine was used to determine loss of viable cells and inhibition of arylamine Nacetyltransferase (NAT) activity in a human colon tumor (adenocarcinoma) cell line. The viable cells were determined by trypan blue exclusion under a light microscope. The NAT activity was measured by high performance liquid chromatography for the amounts of N-acetyl-2-minofluorene (AAF), N-acetyl-p-aminobenzoic acid (N-Ac-PABA), and the remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). The viability and NAT activity in a human colon tumor cell line was inhibited by berberine in a dose-dependent manner, i.e., the higher the concentration of berberine, the higher the inhibition of NAT activity and cell death. The NAT activities measured in the intact human colon tumor cells were decreased over 50% by AAF and NAc-PABA production from acetylation of AF and PABA. The apparent values of Km and Vmax of NAT from colon tumor cells were also inhibited by berberine in cytosols and in intact cells. This report is the first to show that berberine did affect human colon tumor cell NAT activity.

scholarly journals Plasma Treatment of Ovarian Cancer Cells Mitigates Their Immuno-Modulatory Products Active on THP-1 Monocytes

Plasma ◽  
2018 ◽  
Vol 1 (1) ◽  
pp. 201-217 ◽  
Author(s):  
Sander Bekeschus ◽  
Can Wulf ◽  
Eric Freund ◽  
Dominique Koensgen ◽  
Alexander Mustea ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cell ◽  
Plasma Treatment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Expression Patterns ◽  
Cell Phenotype ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Ovarian Carcinomas

Cancers modulate their microenvironment to favor their growth. In particular, monocytes and macrophages are targeted by immuno-modulatory molecules installed by adjacent tumor cells such as ovarian carcinomas. Cold physical plasma has recently gained attention as innovative tumor therapy. We confirmed this for the OVCAR-3 and SKOV-3 ovarian cancer cell lines in a caspase 3/7 independent and dependent manner, respectively. To elaborate whether plasma exposure interferes with their immunomodulatory properties, supernatants of control and plasma-treated tumor cells were added to human THP-1 monocyte cultures. In the latter, modest effects on intracellular oxidation or short-term metabolic activity were observed. By contrast, supernatants of plasma-treated cancer cells abrogated significant changes in morphological and phenotypic features of THP-1 cells compared to those cultured with supernatants of non-treated tumor cell counterparts. This included cell motility and morphology, and modulated expression patterns of nine cell surface markers known to be involved in monocyte activation. This was particularly pronounced in SKOV-3 cells. Further analysis of tumor cell supernatants indicated roles of small particles and interleukin 8 and 18, with MCP1 presumably driving activation in monocytes. Altogether, our results suggest plasma treatment to alleviate immunomodulatory secretory products of ovarian cancer cells is important for driving a distinct myeloid cell phenotype.

scholarly journals Resolvins suppress tumor growth and enhance cancer therapy

2017 ◽  
Vol 215 (1) ◽  
pp. 115-140 ◽  
Author(s):  
Megan L. Sulciner ◽  
Charles N. Serhan ◽  
Molly M. Gilligan ◽  
Dayna K. Mudge ◽  
Jaimie Chang ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Tumor Burden ◽  
Cell Debris ◽  
Resolvin D1 ◽  
Multiple Tumor ◽  
Macrophage Phagocytosis

Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Thus, conventional cancer therapy is inherently a double-edged sword. In this study, we show that tumor cells killed by chemotherapy or targeted therapy (“tumor cell debris”) stimulate primary tumor growth when coinjected with a subthreshold (nontumorigenic) inoculum of tumor cells by triggering macrophage proinflammatory cytokine release after phosphatidylserine exposure. Debris-stimulated tumors were inhibited by antiinflammatory and proresolving lipid autacoids, namely resolvin D1 (RvD1), RvD2, or RvE1. These mediators specifically inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumor types. Resolvins counterregulate the release of cytokines/chemokines, including TNFα, IL-6, IL-8, CCL4, and CCL5, by human macrophages stimulated with cell debris. These results demonstrate that enhancing endogenous clearance of tumor cell debris is a new therapeutic target that may complement cytotoxic cancer therapies.

Mechanistic Evaluation of Siplizumab (MEDI-507) Activity on Normal and Malignant T-Lymphocytes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2504-2504 ◽  
Author(s):  
Scott A. Hammond ◽  
Stacy Fuhrmann ◽  
Shannon Roff ◽  
Peter A. Kiener ◽  
Steve Coats ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Nk Cell ◽  
Cell Lineage ◽  
Maximum Tolerated Dose ◽  
Target Antigen ◽  
Dependent Manner ◽  
Two Phase ◽  
Effector Mechanisms

Abstract Siplizumab is a humanized monoclonal antibody that selectively binds human CD2 (huCD2), which is expressed on virtually all cells of the T- or NK-cell lineage. Also, known as MEDI-507, siplizumab is being developed as a potential new treatment for lymphoid malignancies involving T- or NK-cells. Our present study was designed to increase further the mechanistic understanding of siplizumab activity. Preclinical studies demonstrated that siplizumab mediated efficient lysis of malignant T-cells in a concentration-dependent and effector-to-target cell ratio-dependent manner. ADCC contributed prominently to tumor cell clearance whereas complement-mediated killing (CDC) did not. Siplizumab treatment alone was sufficient to trigger limited internalization of its target antigen (CD2) from the surface of tumor cells. Moreover, the efficiency of CD2 internalization was increased when such studies were carried out in the presence of an activated monocyte cell line (THP-1) bearing Fcg receptors and incapable of mediating ADCC, and suggested that CD2 clearance from the cell surface can be distinguished from host effector mechanisms. CD2 has been long known to confer both inhibitory and stimulatory signals and we reasoned that target internalization might disrupt survival signals independent of host effector activity. Consistent with this concept, siplizumab treatment in the absence of effector cells transduced apoptotic signals as indicated by multiple standard markers of tumor cell apoptosis , including activation of caspase 3 activity and an increase in tumor cells with a sub-G1 DNA content. In addition, the use of transgenic mouse models demonstrated that intravenous administration of siplizumab caused a rapid (≤ 24 hours) but transient reduction in the number of peripheral huCD2-positive T-cells. The number of T-cells gradually recovered to normal levels within 30 days of treatment. In contrast, siplizumab treatment did not alter the number of CD19-positive B-cells. These results indicate that siplizumab can utilize host effector mechanisms (ADCC) to facilitate malignant T-cell elimination. Our present findings also suggest that siplizumab can mediate changes in CD2 expression or function that result in apoptosis of CD2-positive tumor cells. In light of this potent anti-tumor activity, two Phase I dose escalation trials (MI-CP099 and MI-CP107) are ongoing to assess the maximum tolerated dose and safety of siplizumab in patients with CD2-positive T- and NK-cell malignancies.

NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, prevents breast cancer metastasis in vivo

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13163-13163 ◽  
Author(s):  
E. Kawahara ◽  
O. Ohmori ◽  
K. Nonomura ◽  
Y. Murakami ◽  
D. Tomioka ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Small Molecule ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Dual Inhibitor ◽  
Normal Cells ◽  
Dose Dependent

13163 Background: Focal Adhesion Kinase (FAK) and Insulin-like Growth Factor-1 Receptor (IGF-IR) kinase are attractive anti-cancer drug targets because they are both drivers of tumor cell proliferation, migration, and survival. Although virtually every cell type expresses FAK, it is generally overexpressed in tumor cells. FAK levels are greatest in highly metastatic tumors. A selective FAK inhibitor would be expected to halt or kill invasive tumor cells, and potentially interfere with normal cell migration (e.g. endothelial cells). IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: NVP-TAE226, a novel small molecule developed as an inhibitor of FAK, was evaluated in kinase enzymatic assays, cell-based kinase assays and 4T1 metastatic breast carcinoma in vivo model. Results: NVP-TAE226 inhibits FAK with low nanomolar IC50 values in a purified kinase enzymatic assay. In cell-based kinase assays, FAK and IGF-IR kinase were inhibited with an IC50 range of 100 to 300 nM compared to the other kinases tested which were >10-fold less sensitive. Oral administration of NVP-TAE226 inhibited 4T1 murine breast tumor growth and metastasis to the lung in a dose-dependent manner. The compound was well tolerated in mice as determined by measuring changes in body weight. The highest dose of 100 mg/kg, qd, 5x/week showed T/C value of 18%. Inhibition of FAK autophosphorylation at Y397 and Akt phosphorylation at Serine473 was observed in a dose-dependent manner in 4T1 breast carcinoma. Conclusions: NVP-TAE226 represents a novel class of selective and small molecule kinase inhibitors that have potential clinical applications with a potent in vivo activity. [Table: see text]

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