scholarly journals The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells

2021 ◽  
Vol 14 (8) ◽  
pp. 820
Author(s):  
Angéla Takács ◽  
Zsófia Szász ◽  
Márton Kalabay ◽  
Péter Bárány ◽  
Antal Csámpai ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Side Effects ◽  
Cell Surface ◽  
Tumor Therapy ◽  
Death Receptor ◽  
Melanoma Cells ◽  
Synergistic Activity ◽  
Death Receptor 5 ◽  
Synergistic Combinations

Combination antitumor treatments are essential parts of modern tumor therapy as—compared to monotherapies—(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of bortezomib (BOZ) in A2058 melanoma cells. Unfortunately, dose-related side effects are common during BOZ therapy, which could be prevented by reducing the dose of BOZ. This study aimed to characterize synergistic combinations of BOZ with a TRAIL (TNF-related apoptosis-inducing ligand) -inducing compound (TIC10), where the doses can be cut down but the efficacy is preserved. Endpoint cell viability assays were performed on A2058 cells, and synergism of BOZ and TIC10 was observed after 72 h. Synergism was further validated in a real-time impedimetric assay, and our results showed that BOZ-treated melanoma cells survived the treatment, an effect not registered in the co-treatments. Treatment with the combinations resulted in increased apoptosis, which was not accompanied by enhanced LDH release. Nevertheless, the expression of death receptor 5 (DR5) was increased on the cell surface without transcriptional regulation. In summary, our findings support the theory that the application of BOZ and TIC10 in combination could provide higher efficacy in vitro.

scholarly journals HuR’s post-transcriptional regulation of death receptor 5 in pancreatic cancer cells

2012 ◽  
Vol 13 (10) ◽  
pp. 946-955 ◽  
Author(s):  
Danielle M. Pineda ◽  
David W. Rittenhouse ◽  
Christopher C. Valley ◽  
Joseph A. Cozzitorto ◽  
Richard A. Burkhart ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcriptional Regulation ◽  
Cancer Cells ◽  
Death Receptor ◽  
Death Receptor 5 ◽  
Pancreatic Cancer Cells ◽  
Post Transcriptional Regulation

IGM-8444 as a potent agonistic Death Receptor 5 (DR5) IgM antibody: Induction of tumor cytotoxicity, combination with chemotherapy and in vitro safety profile.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3595-3595
Author(s):  
Beatrice Wang ◽  
Ling Wang ◽  
Tasnim Kothambawala ◽  
Susan Calhoun ◽  
Thomas Matthew ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Safety Profile ◽  
Single Agent ◽  
Death Receptor ◽  
Standard Of Care ◽  
In Vitro Cytotoxicity ◽  
Death Receptor 5 ◽  
Dose Dependent

3595 Background: Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF) receptor superfamily that multimerizes when bound to its ligand, TNF-related apoptosis inducing ligand (TRAIL), to activate the extrinsic apoptotic pathway. DR5 is broadly expressed on solid and hematologic cancers and has been targeted with both recombinant TRAIL and agonistic antibodies in the clinic. However, these therapeutics have generally been unsuccessful due to toxicity or lack of efficacy. We have developed a multivalent IgM DR5 agonist, IGM-8444, that multimerizes DR5 to selectively and potently induce tumor cell apoptosis while maintaining tolerability. Methods: IGM-8444 is an engineered, pentameric IgM antibody with 10 binding sites specific for DR5. Human tumor cell lines or hepatocytes were evaluated in vitro for dose dependent IGM-8444 induced cytotoxicity. The efficacy of IGM-8444 was evaluated with or without chemotherapy, in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse tumor models, with IGM-8444 administered at various dose levels and schedules when tumors reached approximately 100 mm3. Sera and tumors were analyzed for biomarkers of tumor apoptosis. Results: In vitro cytotoxicity assays identified IGM-8444 activity across cell lines from 18 solid and hematologic malignancies. In IGM-8444 partially resistant cell lines, combination with chemotherapy or a Bcl2 inhibitor enhanced in vitro cytotoxicity. IGM-8444 was efficacious as a monotherapy in CDX and PDX tumor models including colorectal, lung, and gastric indications. In a gastric PDX model, IGM-8444 induced complete and durable dose-dependent tumor regressions. In vivo, combination of IGM-8444 with standard-of-care chemotherapies, such as irinotecan, led to enhanced efficacy. IGM-8444 administration increased markers of tumor apoptosis, identifying potential clinical pharmacodynamic biomarkers. At doses several log-fold higher than efficacious doses, IGM-8444 demonstrated a favorable single agent in vitro safety profile, with little to no in vitro cytotoxicity observed using primary human hepatocytes from multiple donors. Conclusions: These data support the clinical development of IGM-8444 in both solid and hematological malignancies as a single agent and in combination with standard of care therapy. IGM-8444 is projected for IND filing in 2020.

scholarly journals Indomethacin Sensitizes TRAIL-Resistant Melanoma Cells to TRAIL-Induced Apoptosis through ROS-Mediated Upregulation of Death Receptor 5 and Downregulation of Survivin

2014 ◽  
Vol 134 (5) ◽  
pp. 1397-1407 ◽  
Author(s):  
Anfernee Kai-Wing Tse ◽  
Hui-Hui Cao ◽  
Chi-Yan Cheng ◽  
Hiu-Yee Kwan ◽  
Hua Yu ◽  
...  
Keyword(s):  
Death Receptor ◽  
Melanoma Cells ◽  
Death Receptor 5 ◽  
Induced Apoptosis

scholarly journals Circulating Tumor Cells Develop Resistance to TRAIL-Induced Apoptosis through Autophagic Removal of Death Receptor 5: Evidence from an In Vitro Model

2018 ◽  
Author(s):  
Julianne D. Twomey ◽  
Baolin Zhang
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Immune Surveillance ◽  
Death Receptor ◽  
Metastatic Potential ◽  
Breast Cancer Cell Lines ◽  
Autophagic Flux ◽  
Death Receptor 5 ◽  
Molecular Features

Circulating tumor cells (CTCs) in the peripheral blood are the precursors to distant metastasis but the underlying mechanisms are poorly understood.  This study aims at understanding the molecular features within CTCs in relation to their metastatic potential.  Using in vitro CTC models, in which breast cancer cell lines are cultured in non-adherent conditions simulating the microenvironment in the blood stream, we found that suspension culture resulted in resistance to TNF-related apoptosis inducing ligand (TRAIL)-mediated cell death. Such a resistance was directly correlated with a reduction in surface and total levels of DR5 protein. In the non-adherent state, cells underwent rapid autophagic flux characterized by an accumulation of autophagosome organelles. Notably, DR5 was translocated to autophagosomes and underwent lysosomal degradation.  Our data suggest that CTCs may evade TNF cytokine mediated immune surveillance through downregulation of DR expression. The data warrants further studies in cancer patients to find the status of DRs and other molecular features within primary CTCs in relation to disease progression or chemoresistance.

scholarly journals Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2489
Author(s):  
Aleksandr Ianevski ◽  
Rouan Yao ◽  
Eva Zusinaite ◽  
Laura Sandra Lello ◽  
Sainan Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Side Effects ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Clinical Development ◽  
Rna Transcription ◽  
Synthesis And Processing ◽  
Synergistic Combinations

Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα–remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.

scholarly journals DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment

2020 ◽  
Author(s):  
Mamta Kumari ◽  
Praveen T. Krishnamurthy ◽  
Sai kiran S. S. Pinduprolu ◽  
Piyong Sola
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Side Effects ◽  
Notch Signaling ◽  
Death Receptor ◽  
Death Receptor 5 ◽  
Gamma Secretase ◽  
Extrinsic Pathway ◽  
Cancer Subtypes ◽  
Target Side

Triple-negative breast cancer (TNBC) is the most aggressive and heterogeneous cancer subtypes. High rates of metastasis, poor prognosis, and drug resistance are the major problems associated with TNBC. The current chemotherapeutics eliminate only the bulk tumor cells (non-BCSCs) and do not affect breast cancer stem cells (BCSCs). The BCSCs which are left behind after chemotherapy is reported to promote recurrence and metastasis of TNBC. Death receptor-5 (DR-5) is exclusively expressed in TNBCs and mediates the extrinsic pathway of apoptosis. DR-5, therefore, can be exploited for targeted drug delivery and to induce apoptosis. Gamma-secretase mediated Notch signaling in BCSCs regulates its proliferation, differentiation, and metastasis. The endogenous ligand, Delta-like ligand 4 (DLL4), is reported to activate this Notch signaling in TNBC. Blocking this signaling pathway using both gamma-secretase inhibitors (GSIs) and DLL4 monoclonal antibody (mAb) may produce synergistic benefits. Further, the GSIs (DAPT, LY-411575, RO4929097, MK0752, etc.) suffer from poor bioavailability and off-target side effects such as diarrhea, suppression of lymphopoiesis, headache, hypertension, fatigue, and ventricular dysfunctions. In this hypothesis, we discuss Solid lipid nanoparticles (SLNs) based drug delivery systems containing GSIs and surface modified with DR-5 and DLL4 monoclonal antibodies (mAb) to effectivity target and treat TNBC. The delivery system is designed to deliver the drug cargo precisely to TNBCs through its DR-5 receptors and hence expected to reduce the off-target side effects of GSIs. Further, DLL4 mAb and GSIs are expected to act synergistically to block the Notch signal mediated BCSCs proliferation, differentiation, and metastasis.

scholarly journals ID: 1015 Taraxacum officinale (dandelion) extract efficiently inhibited the breast cancer stem cell proliferation

2017 ◽  
Vol 4 (S) ◽  
pp. 89 ◽  
Author(s):  
Ngu Van Trinh ◽  
Nghi Doan-Phuong Dang ◽  
Diem Hong Tran ◽  
Phuc Van Pham
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
3D Model ◽  
Death Receptor ◽  
Taraxacum Officinale ◽  
Death Receptor 5 ◽  
Enhanced Production ◽  
2D Model

Introduction: Breast cancer stem cells (BCSCs) play an important role in breast cancer initiation, metastasis, recurrence, and drug resistance. Therefore, targeting BCSCs is an essential strategy to suppress cancer growth. This study aimed to evaluate the effects of dandelion Taraxacum officinale extracts on BCSC proliferation in vitro in 2D and 3D cell culture platforms. Methods: The BCSCs were maintained understandard conditions, verified for expression of CD44 and CD24 surface markers, and transfected with GFP before use in experiments. In the 2D model, the BCSCs were cultured as adherent cells in standard culture plates; in the 3D model, the BCSCs were cultured on low-adherent plates to form spheroids. The effect of Dandelion extracts on proliferation of BCSC was assessed by evaluating induction of cell death, expression of genes of death receptor signaling pathways, and production of reactive oxygen species (ROS) by BCSCs. Results: BCSCs formed spheroids as microtumors in vitro and exhibited some in vivo characteristics of tumors, such as increased expression of N-cadherin and Slug, decreased expression of E-cadherin, capacity to invade into the extracellular matrix (ECM), and presence of a hypoxic environment at the core of tumor spheroids. The dandelion extracts significantly inhibited BCSC proliferation in both two-dimensional (2D) and three-dimensional (3D) models of BCSCs. However, the IC50 value of dandelion extracts in BCSCs in the 3D model was much higher than that in the 2D model. The results also demonstrated that BCSCs treated with Dandelion extracts showed increased expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor 2 (TRAILR2; i.e. death receptor 5;DR5). Moreover, treatment induced expression of DR4. Treatment with methanol dandelion extract enhanced production of ROS in BCSCs.  Conclusion: Dandelion extracts are promising extracts for the treatment of breast tumors. The effect of methanol dandelion extract was better than that for ethanol extract. Importantly, BCSCs in 3D exhibited stronger drug resistance than those in 2D. In summary, our results indicate the strong potential of dandelion extracts as anti-cancer agents and rational use for drug development.

Sign in / Sign up

Export Citation Format

Share Document