Nanoformulation of PROteolysis TArgeting Chimera targeting ‘undruggable’ c-Myc for the treatment of pancreatic cancer

Nanomedicine ◽  
2020 ◽  
Vol 15 (18) ◽  
pp. 1761-1777 ◽  
Author(s):  
Aishwarya Saraswat ◽  
Manali Patki ◽  
Yige Fu ◽  
Shrikant Barot ◽  
Vikas V Dukhande ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Culture ◽  
Physicochemical Properties ◽  
Therapeutic Strategy ◽  
Caspase 3 ◽  
Physical Stability ◽  
Pancreatic Cancer Cells ◽  
Nanoprecipitation Method ◽  
Apoptotic Marker ◽  
Novel Therapeutic

Aim: To explore the anticancer activity of a novel BRD4 protein degrader ARV-825 (ARV) and its nanoformulation development (ARV-NP) for treatment of pancreatic cancer. Materials & methods: ARV-NP were prepared using nanoprecipitation method and characterized for their physicochemical properties and various anticancer cell culture assays. Results: ARV-NP (89.63 ± 16.39 nm) demonstrated good physical stability, negligible hemolysis and improved half-life of ARV. ARV-NP showed significant cytotoxicity, apoptosis and anticlonogenic effect in pancreatic cancer cells. Significant downregulation of target proteins BRD4, c-Myc, Bcl-2 and upregulation of apoptotic marker cleaved caspase-3 was observed. Most importantly, ARV-NP treatment significantly inhibited the cell viability of 3D tumor spheroids of pancreatic cancer. Conclusion: ARV-NP represents a novel therapeutic strategy for pancreatic cancer.

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

2017 ◽  
Vol 17 (1) ◽  
pp. 183-195 ◽  
Author(s):  
Osamu Shimomura ◽  
Tatsuya Oda ◽  
Hiroaki Tateno ◽  
Yusuke Ozawa ◽  
Sota Kimura ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Surface ◽  
Therapeutic Strategy ◽  
Cancer Targeting ◽  
Drug Conjugate ◽  
Novel Therapeutic

scholarly journals Solanine Induces Mitochondria-Mediated Apoptosis in Human Pancreatic Cancer Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Hongwei Sun ◽  
Chongqing Lv ◽  
Longlong Yang ◽  
Yingxiu Wang ◽  
Qingshun Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Human Pancreatic Cancer ◽  
Mice Model ◽  
Pancreatic Cancer Cells

Steroid alkaloids have been suggested as potential anticancer compounds. However, the underlying mechanisms of how steroid alkaloids inhibit the tumor growth are largely unknown. Here, we reported that solanine, a substance of steroid alkaloids, has a positive effect on the inhibition of pancreatic cancer cell growth in vitro and in vivo. In pancreatic cancer cells and nu/nu nude mice model, we found that solanine inhibited cancer cells growth through caspase-3 dependent mitochondrial apoptosis. Mechanically, solanine promotes the opening of mitochondrial membrane permeability transition pore (MPTP) by downregulating the Bcl-2/Bax ratio; thereafter, Cytochrome c and Smac are released from mitochondria into cytosol to process the caspase-3 zymogen into an activated form. Moreover, we found that the expression of tumor metastasis related proteins, MMP-2 and MMP-9, was also decreased in the cells treated with solanine. Therefore, our results suggested that solanine was an effective compound for the treatment of pancreatic cancer.

scholarly journals Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner

2020 ◽  
Vol 31 (12) ◽  
pp. 1259-1272 ◽  
Author(s):  
Casey J. Latario ◽  
Lori W. Schoenfeld ◽  
Charles L. Howarth ◽  
Laura E. Pickrell ◽  
Fatema Begum ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Culture ◽  
Plasma Membrane ◽  
Cancer Cells ◽  
Actin Filaments ◽  
Dependent Manner ◽  
Tumor Models ◽  
Pancreatic Cancer Cells ◽  
Cell Substrate ◽  
Cancer Line

We identify tumor microtubes (TMTs) and cell-substrate protrusions (CSPs) in a pancreatic cancer line, in cell culture, tumor models, and a subset of primary human tumors. TMTs and CSPs emanate from the lateral plasma membrane and contain actin filaments, microtubules, and cytokeratin. Arp2/3 complex drives two distinct TMT assembly mechanisms.

scholarly journals YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 620 ◽  
Author(s):  
Ling Zhou ◽  
Qiaoyun Wang ◽  
Han Zhang ◽  
Youjie Li ◽  
Shuyang Xie ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Strategy ◽  
Cultured Cells ◽  
Raw Material ◽  
Mechanism Study ◽  
Aporphine Alkaloid ◽  
Pancreatic Cancer Cells ◽  
Lotus Leaves ◽  
Coa Reductase ◽  
Gemcitabine Treatment

Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC.

scholarly journals An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sean A. Hunter ◽  
Brianna J. McIntosh ◽  
Yu Shi ◽  
R. Andres Parra Sperberg ◽  
Chie Funatogawa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Animal Models ◽  
Cancer Treatment ◽  
Leukemia Inhibitory Factor ◽  
Therapeutic Strategy ◽  
Inhibitory Factor ◽  
Wild Type ◽  
High Affinity ◽  
Mediated Effects ◽  
Pancreatic Cancer Cells

AbstractLeukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy. This engineered ‘ligand trap’, fused to an antibody Fc-domain, has ~50-fold increased affinity (~20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. These results, and the lack of apparent toxicity observed in animal models, further highlights ligand traps as a promising therapeutic strategy for cancer treatment.

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