Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors

Anders Olsson, Anders Björk, Johan Vallon-Christersson, John Tod Isaacs, Tomas Leanderson

Research output: Contribution to journalArticle

Abstract

Background: The orally active quinoline-3-carboxamide tasquinimod [ABR-215050; CAS number 254964-60-8), which currently is in a phase II-clinical trial in patients against metastatic prostate cancer, exhibits anti-tumor activity via inhibition of tumor angiogenesis in human and rodent tumors. To further explore the mode of action of tasquinimod, in vitro and in vivo experiments with gene microarray analysis were performed using LNCaP prostate tumor cells. The array data were validated by real-time semiquantitative reversed transcriptase polymerase chain reaction (sqRT-PCR) and protein expression techniques.Results: One of the most significant differentially expressed genes both in vitro and in vivo after exposure to tasquinimod, was thrombospondin-1 (TSP1). The up-regulation of TSP1 mRNA in LNCaP tumor cells both in vitro and in vivo correlated with an increased expression and extra cellular secretion of TSP1 protein. When nude mice bearing CWR-22RH human prostate tumors were treated with oral tasquinimod, there was a profound growth inhibition, associated with an up-regulation of TSP1 and a down- regulation of HIF-1 alpha protein, androgen receptor protein (AR) and glucose transporter-1 protein within the tumor tissue. Changes in TSP1 expression were paralleled by an anti-angiogenic response, as documented by decreased or unchanged tumor tissue levels of VEGF (a HIF-1 alpha down stream target) in the tumors from tasquinimod treated mice.Conclusions: We conclude that tasquinimod-induced up-regulation of TSP1 is part of a mechanism involving down-regulation of HIF1α and VEGF, which in turn leads to reduced angiogenesis via inhibition of the "angiogenic switch", that could explain tasquinimods therapeutic potential.

Original languageEnglish (US)
Article number107
JournalMolecular Cancer
Volume9
DOIs
StatePublished - May 17 2010

Fingerprint

Thrombospondin 1
Prostate
Neoplasms
Up-Regulation
Proteins
Vascular Endothelial Growth Factor A
Down-Regulation
tasquinimod
quinoline-3-carboxamide
Phase II Clinical Trials
Facilitative Glucose Transport Proteins
Androgen Receptors
DNA-Directed RNA Polymerases
Microarray Analysis
Nude Mice
Genes
Rodentia
Prostatic Neoplasms
Polymerase Chain Reaction
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology

Cite this

Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors. / Olsson, Anders; Björk, Anders; Vallon-Christersson, Johan; Isaacs, John Tod; Leanderson, Tomas.

In: Molecular Cancer, Vol. 9, 107, 17.05.2010.

Research output: Contribution to journalArticle

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abstract = "Background: The orally active quinoline-3-carboxamide tasquinimod [ABR-215050; CAS number 254964-60-8), which currently is in a phase II-clinical trial in patients against metastatic prostate cancer, exhibits anti-tumor activity via inhibition of tumor angiogenesis in human and rodent tumors. To further explore the mode of action of tasquinimod, in vitro and in vivo experiments with gene microarray analysis were performed using LNCaP prostate tumor cells. The array data were validated by real-time semiquantitative reversed transcriptase polymerase chain reaction (sqRT-PCR) and protein expression techniques.Results: One of the most significant differentially expressed genes both in vitro and in vivo after exposure to tasquinimod, was thrombospondin-1 (TSP1). The up-regulation of TSP1 mRNA in LNCaP tumor cells both in vitro and in vivo correlated with an increased expression and extra cellular secretion of TSP1 protein. When nude mice bearing CWR-22RH human prostate tumors were treated with oral tasquinimod, there was a profound growth inhibition, associated with an up-regulation of TSP1 and a down- regulation of HIF-1 alpha protein, androgen receptor protein (AR) and glucose transporter-1 protein within the tumor tissue. Changes in TSP1 expression were paralleled by an anti-angiogenic response, as documented by decreased or unchanged tumor tissue levels of VEGF (a HIF-1 alpha down stream target) in the tumors from tasquinimod treated mice.Conclusions: We conclude that tasquinimod-induced up-regulation of TSP1 is part of a mechanism involving down-regulation of HIF1α and VEGF, which in turn leads to reduced angiogenesis via inhibition of the {"}angiogenic switch{"}, that could explain tasquinimods therapeutic potential.",
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