Article

Influence of glioma tumour microenvironment on the transport of ANG1005 via low-density lipoprotein receptor-related protein 1

Laboratoire de Médecine Moléculaire, Chemistry Department, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, Canada.
British Journal of Cancer (Impact Factor: 4.84). 11/2011; 105(11):1697-707. DOI: 10.1038/bjc.2011.427
Source: PubMed

ABSTRACT

ANG1005 consists of three molecules of paclitaxel conjugated via ester bonds to the 19-amino-acid peptide Angiopep-2. The new chemical agent has been shown to cross the blood-brain barrier (BBB) by receptor-mediated transcytosis via low-density lipoprotein receptor-related protein 1 (LRP1). The experiments here examined the role of LRP1 in the subsequent endocytosis of drug into cancer cells.
Localisation of ANG1005 and Angiopep-2 was examined by immunohistochemistry and in-vivo near-infrared fluorescence imaging in mice carrying orthotopic glioma tumours. Transport of ANG1005 and Angiopep-2 was examined in U87 glioblastoma cell lines.
Systemically administered ANG1005 and Cy5.5Angiopep-2 localised to orthotopic glioma tumours in mice. The glioma transplants correlated with high expression levels of LRP1. Decreasing LRP1 activity, by RNA silencing or LRP1 competitors, decreased uptake of ANG1005 and Angiopep-2 into U87 glioblastoma cells. Conversely, LRP1 expression and endocytosis rates for ANG1005 and Angiopep-2 increased in U87 cells under conditions that mimicked the microenvironment near aggressive tumours, that is, hypoxic and acidic conditions.
ANG1005 might be a particularly effective chemotherapeutic agent for the wide array of known LRP1-expressing brain and non-brain cancers, in particular those with an aggressive phenotype.

Download full-text

Full-text

Available from: Danica Stanimirovic
  • Source
    • "uice for chemotherapeutic agents into the brain as BBB penetration is currently the Achilles ' heel in brain cancer therapies ( Jovčevska et al . , 2013 ) . Uptake of paclitaxel through the BBB followed by endocytosis into tumor cells was shown to be increased after conjugating the taxane paclitaxel to a 19 amino acid sequence named angiopep - 2 ( Bertrand et al . , 2011 ) . This peptide was derived from the Kunitz domain , a known ligand of LRP1 . A phase I clinical study showed that this conjugate ( GRN1005 ) is well tolerated ( Kurzrock et al . , 2012 ; Drappatz et al . , 2013 ) . Therapeutic concentrations could be reached in the tumor and three patients where prior taxane therapy was unsuccessful s"
    [Show abstract] [Hide abstract]
    ABSTRACT: The membrane protein low-density lipoprotein receptor related-protein 1 (LRP1) has been attributed a role in cancer. However, its presumably often indirect involvement is far from understood. LRP1 has both endocytic and signaling activities. As a matricellular receptor it is involved in regulation, mostly by clearing, of various extracellular matrix degrading enzymes including matrix metalloproteinases, serine proteases, protease inhibitor complexes, and the endoglycosidase heparanase. Furthermore, by binding extracellular ligands including growth factors and subsequent intracellular interaction with scaffolding and adaptor proteins it is involved in regulation of various signaling cascades. LRP1 expression levels are often downregulated in cancer and some studies consider low LRP1 levels a poor prognostic factor. On the contrary, upregulation in brain cancers has been noted and clinical trials explore the use of LRP1 as cargo receptor to deliver cytotoxic agents. This mini-review focuses on LRP1’s role in tumor growth and metastasis especially by modulation of the extracellular tumor environment. In relation to this role its diagnostic, prognostic and therapeutic potential will be discussed.
    Full-text · Article · Nov 2015 · Frontiers in Pharmacology
  • Source
    • "Angiochem, a Canadian clinical stage biotechnology company, has reported positive results for peptide–drug conjugates that target the LRP1-mediated uptake pathway to cross the blood– brain barrier into tumor cells for the treatment of brain cancers, including glioblastoma and brain metastases, in phase 1 and 2 clinical trials (Bertrand et al., 2011; Pharmalive website, http:// www.pharmalive.com/News/Index.cfm?articleid=845262, accessed 19 June 2012). The role of emodin (6-methyl-1, 3, 8-trihydroxyanthraquinone), a molecule found in certain plants, has been explored by many researchers for its antiproliferative activity in cancer cell lines of the breast (Huang et al., 2009), colon (Lee et al., 2005), cervix (Srinivas et al., 2003), liver (Shieh et al., 2004; Hsu et al., 2010), lung (Su et al., 2005; Lai et al., 2009) and prostate (Cha et al., 2005; Zhou et al., 2006), and leukemia (Chen et al., 2002; Chun-Guang et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study explores the link between the antiproliferative activity of emodin through the generation of reactive oxygen species (ROS) in various cancer cell lines and the expression of the androgen receptor (AR) in the prostate cancer cell lines LNCaP (androgen-sensitive) and PC-3 (androgen-refractory), as well as the pro-metastatic low-density lipoprotein receptor-related protein 1 (LRP1) in the above prostate cancer cells and the nonprostate cell lines A549 (lung), HCT-15 (colon) and MG-63 (bone) under normoxic and hypoxia-like conditions. Among all cell lines, emodin showed most growth inhibition in LNCaP, followed by A549. The mechanism of cytotoxicity of emodin was postulated to be the widely reported ROS generation, based on the observations of poor in vitro radical-scavenging activity and increased growth inhibition of emodin by ascorbic acid (AA) pre-treatment owing to the additive effects of ROS generation by emodin and pro-oxidant effects of AA. Emodin downregulated AR in LNCaP under normoxic and hypoxia-like conditions (simulated by CoCl(2) ) and LRP1 under normoxia. Emodin upregulated LRP1 in other cell lines, except HCT-15, under normoxic, and even more markedly under hypoxia-like conditions. The downregulation of AR in LNCaP and upregulation of LRP1 in all cell lines, except HCT-15, under hypoxia-like conditions along with growth inhibition by emodin, suggests that emodin may be a useful therapeutic option against androgen-sensitive prostate cancer and other such LRP1-expressing cancers to attempt the targeting of the elevated LRP1 levels to allow the uptake of emodin and/or any other accompanying therapeutic agents by LRP1. Copyright © 2012 John Wiley & Sons, Ltd.
    Full-text · Article · Mar 2014 · Journal of Applied Toxicology
  • Source
    • "ANG1007, the Angiopep-5 conjugated to three doxorubicin molecules, killed cancer cell lines in vitro and crossed the BBB with a dramatically high influx rate [113]. In recent years, much effort has been made to use Angiopeps to deliver drugs or nanoparticles across the BBB to the CNS, showing that Angiopep-mediated targeting is one of the most promising ways to reach the CNS for treatment of brain cancer or brain metastases [114-116]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The blood-brain barrier (BBB), a dynamic and complex barrier formed by endothelial cells, can impede the entry of unwanted substances - pathogens and therapeutic molecules alike - into the central nervous system (CNS) from the blood circulation. Taking into account the fact that CNS-related diseases are the largest and fastest growing unmet medical concern, many potential protein- and nucleic acid-based medicines have been developed for therapeutic purposes. However, due to their poor ability to cross the BBB and the plasma membrane, the above-mentioned bio-macromolecules have limited use in treating neurological diseases. Finding effective, safe, and convenient ways to deliver therapeutic molecules into the CNS is thus urgently required. In recent decades, much effort has been expended in the development of drug delivery technologies, of which cell-penetrating peptides (CPPs) have the most promising potential. The present review covers the latest advances in CPP delivery technology, and provides an update on their use in CNS-targeted drug delivery.
    Full-text · Article · Mar 2013 · Current Neuropharmacology
Show more