scholarly journals New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Cyndia Charfi ◽  
Michel Demeule ◽  
Jean-Christophe Currie ◽  
Alain Larocque ◽  
Alain Zgheib ◽  
...  

Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by genetically deregulated cancer cells and is often associated with high tumor grade and cancer therapy resistance. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumors, and contributes also in part to metastasis. VM has been observed in ovarian cancer and in triple negative breast cancer (TNBC) and shown to correlate with decreased overall cancer patient survival. Thus, strategies designed to inhibit VM may improve cancer patient treatments. In this study, sortilin (SORT1) receptor was detected in in vitro 3D capillary-like structures formed by ES-2 ovarian cancer and MDA-MB-231 TNBC-derived cells when grown on Matrigel. SORT1 gene silencing or antibodies directed against its extracellular domain inhibited capillary-like structure formation. In vitro, VM also correlated with increased gene expression of matrix metalloproteinase-9 (MMP-9) and of the cancer stem cell marker CD133. In vivo ES-2 xenograft model showed PAS+/CD31- VM structures (staining positive for both SORT1 and CD133). TH1904, a Doxorubicin-peptide conjugate that is internalized by SORT1, significantly decreased in vitro VM at low nM concentrations. In contrast, VM was unaffected by unconjugated Doxorubicin or Doxil (liposomal Doxorubicin) up to μM concentrations. TH1902, a Docetaxel-peptide conjugate, altered even more efficiently in vitro VM at pM concentrations. Overall, current data evidence for the first time that 1) SORT1 itself exerts a crucial role in both ES-2 and MDA-MB-231 VM, and that 2) VM in these cancer cell models can be efficiently inhibited by the peptide-drug conjugates TH1902/TH1904. These new findings also indicate that both peptide-drug conjugates, in addition to their reported cytotoxicity, could possibly inhibit VM in SORT1-positive TNBC and ovarian cancer patients.

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 849
Author(s):  
Yayu Wang ◽  
Yadan Li ◽  
Jieqiong Cao ◽  
Qilin Meng ◽  
Xiaocen Li ◽  
...  

A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide–drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 °C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide–drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B–DM1 can be developed into a potential PDC for tumor treatment in the future.


Author(s):  
Jiaqi Zhou ◽  
Yuanyuan Li ◽  
Wenlong Huang ◽  
Wei Shi ◽  
Hai Qian

2018 ◽  
Vol 29 (2) ◽  
pp. 1806058 ◽  
Author(s):  
Rui Chen ◽  
Jingjing Wang ◽  
Chen Qian ◽  
Yujie Ji ◽  
Chenqi Zhu ◽  
...  

2015 ◽  
Vol 23 (5) ◽  
pp. 907-917 ◽  
Author(s):  
Geoffrey Y Berguig ◽  
Anthony J Convertine ◽  
Shani Frayo ◽  
Hanna B Kern ◽  
Erik Procko ◽  
...  

PLoS ONE ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. e0158208 ◽  
Author(s):  
Øystein Helland ◽  
Mihaela Popa ◽  
Katharina Bischof ◽  
Bjørn Tore Gjertsen ◽  
Emmet McCormack ◽  
...  

2014 ◽  
Vol 191 ◽  
pp. 123-130 ◽  
Author(s):  
Zhipeng Chen ◽  
Pengcheng Zhang ◽  
Andrew G. Cheetham ◽  
Jae Hyon Moon ◽  
James W. Moxley ◽  
...  

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