scholarly journals MADD silencing enhances anti-tumor activity of TRAIL in anaplastic thyroid cancer

2019 ◽  
Vol 26 (6) ◽  
pp. 551-563 ◽  
Author(s):  
Shikha Saini ◽  
Lakshmi Sripada ◽  
Kiara Tulla ◽  
Guilin Qiao ◽  
Nicholas Kunda ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Cell ◽  
Combination Treatment ◽  
Cellular Localization ◽  
Anaplastic Thyroid Cancer ◽  
Cellular Growth ◽  
Therapeutic Drug ◽  
Orthotopic Mouse Model ◽  
Trail Resistance

ATC is an aggressive disease with limited therapeutic options due to drug resistance. TRAIL is an attractive anti-cancer therapy that can trigger apoptosis in a cancer cell-selective manner. However, TRAIL resistance is a major clinical obstacle for its use as a therapeutic drug. Previously, we demonstrated that MADD is a cancer cell pro-survival factor that can modulate TRAIL resistance. However, its role, if any, in overcoming TRAIL resistance in ATC is unknown. First, we characterized ATC cell lines as either TRAIL resistant, TRAIL sensitive or moderately TRAIL sensitive and evaluated MADD expression/cellular localization. We determined the effect of MADD siRNA on cellular growth and investigated its effect on TRAIL treatment. We assessed the effect of combination treatment (MADD siRNA and TRAIL) on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels. The effect of combination treatment on tumor growth was assessed in vivo. We found increased levels of MADD in ATC cells relative to Nthy-ori 3-1. MADD protein localizes in the cytosol (endoplasmic reticulum and Golgi body) and membrane. MADD knockdown resulted in spontaneous cell death that was synergistically enhanced when combined with TRAIL treatment in otherwise resistant ATC cells. Combination treatment resulted in a significant reduction in MMP and enhanced generation of ROS indicating the putative mechanism of action. In an orthotopic mouse model of TRAIL-resistant ATC, treatment with MADD siRNA alone reduced tumor growth that, when combined with TRAIL, resulted in significant tumor regressions. We demonstrated the potential clinical utility of MADD knockdown in sensitizing cells to TRAIL-induced apoptosis in ATC.

scholarly journals Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo

2017 ◽  
Vol 8 ◽  
pp. 493 ◽  
Author(s):  
Tasleem Arif ◽  
Lilia Vasilkovsky ◽  
Yael Refaely ◽  
Alexander Konson ◽  
Varda Shoshan-Barmatz
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Cancer Cell Proliferation

scholarly journals Polar biophenolics in sweet potato greens extract synergize to inhibit prostate cancer cell proliferation and in vivo tumor growth

2013 ◽  
Vol 34 (9) ◽  
pp. 2039-2049 ◽  
Author(s):  
Sushma R. Gundala ◽  
Chunhua Yang ◽  
N. Lakshminarayana ◽  
Ghazia Asif ◽  
Meenakshi V. Gupta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Sweet Potato ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Proliferation

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 Inhibition of platelet activation prevents the P‐selectin and integrin‐dependent accumulation of cancer cell microparticles and reduces tumor growth and metastasis in vivo

2014 ◽  
Vol 136 (2) ◽  
pp. 462-475 ◽  
Author(s):  
Soraya Mezouar ◽  
Roxane Darbousset ◽  
Françoise Dignat‐George ◽  
Laurence Panicot‐Dubois ◽  
Christophe Dubois
Keyword(s):  
Tumor Growth ◽  
Cancer Cell ◽  
Platelet Activation ◽  
Tumor Growth And Metastasis

scholarly journals Crenolanib, a PDGFR inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo

2014 ◽  
pp. 1761 ◽  
Author(s):  
Ping Wang ◽  
Liqiang Song ◽  
Hui Ge ◽  
Pule Jin ◽  
Yifang Jiang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Lung Cancer Cell

scholarly journals Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo

2014 ◽  
Vol 3 ◽  
pp. e159 ◽  
Author(s):  
Tasleem Arif ◽  
Lilia Vasilkovsky ◽  
Yael Refaely ◽  
Alexander Konson ◽  
Varda Shoshan-Barmatz
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Cancer Cell Proliferation

scholarly journals An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity

2021 ◽  
Author(s):  
Joshua J Gruber ◽  
Amith Rangarajan ◽  
Tristan Chou ◽  
Benjamin S. Geller ◽  
Selene Banuelos ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Small Molecule ◽  
Cancer Metabolism ◽  
Human Cancer ◽  
Small Molecule Inhibitor ◽  
Cellular Growth ◽  
Acetyl Coa ◽  
Molecule Inhibitor

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H3:H4 tetramers in the cytoplasm. It may have a role in cancer metabolism by linking cytoplasmic production of acetyl-CoA to nuclear acetyl flux. This is because the HAT1 di-acetylation mark is not propagated in chromatin and instead is de-acetylated after nascent histone insertion into chromatin. Thus, HAT1 likely provides a nuclear source of free acetate that may be recycled to acetyl-CoA for nuclear acetylation reactions. Correspondingly, suppression of HAT1 protein expression impairs tumor growth. To ascertain whether targeting HAT1 is a viable anti-cancer treatment strategy we sought to identify small molecule inhibitors of HAT1. We developed a high-throughput HAT1 acetyl-click assay to facilitate drug discovery and enzymology. Screening of small molecules computationally predicted to bind the active site led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity by competing with acetyl-CoA binding. These hits were refined by synthesis and testing over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl sidechain improved enzymatic potency and cellular growth suppression. These efforts resulted in a lead compound (JG-2016) that suppressed growth of human cancer cells lines in vitro and impaired tumor growth in vivo. This is the first report of a small molecule inhibitor of the HAT1 enzyme complex and represents a step towards targeting this pathway for cancer therapy.

Sign in / Sign up

Export Citation Format

Share Document