Effect of IN-1130, a Small Molecule Inhibitor of Transforming Growth Factor-β Type I Receptor/Activin Receptor-Like Kinase-5, on Prostate Cancer Cells

Geun Taek Lee, Jun Hyuk Hong, Thomas J. Mueller, John A. Watson, Cheol Kwak, Youn Young Sheen, Dae Kee Kim, Seong Jin Kim, Isaac Yi Kim

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Purpose: Transforming growth factor-β is a potent immune suppressor that is over expressed by most malignant cells to evade the host immune response. Thus, a potential anticancer therapeutic strategy is the inhibition of transforming growth factor-β signaling. Materials and Methods: We investigated the specificity and the antitumor effect of IN-1130, a novel small molecule inhibitor of the transforming growth factor-β type I receptor ALK-5. Results: IN-1130 inhibited transforming growth factor-β induced cell death and gene transcriptional activity in a concentration dependent manner in the human hepatoma cell line HepG2. Simultaneously immunoblot analysis demonstrated that IN-1130 inhibited the Smad2 phosphorylation induced by transforming growth factor-β. To determine the specificity of IN-1130 for transforming growth factor-β signaling the effect on active and bone morphogenic protein signaling was subsequently investigated. Results demonstrated that IN-1130 did not inhibit bone morphogenic protein signaling. However, active signaling was blocked by IN-1130 in a concentration dependent manner. Furthermore, immunoblot analysis for phospho-Smad2 following transfection with constitutively active ALK-1 to 7 demonstrated that IN-1130 inhibited ALK-4 (active receptor type IB), 5 (TβRI) and 7 (nodal type I receptor). To investigate the antitumor effect of IN-1130 WT mice were injected subcutaneously with the murine prostate cancer cell line Tramp C2. Seven days later IN-1130 was administered intraperitoneally daily for 30 days. Results demonstrated a dramatic decrease in tumor volume in association with an enhanced immune response in the treatment group. Conclusions: Taken together these results demonstrate that IN-1130 is a relatively nontoxic inhibitor of ALK-4/5/7 that may potentially treat prostate cancer.

Original languageEnglish
Pages (from-to)2660-2667
Number of pages8
JournalJournal of Urology
Volume180
Issue number6
DOIs
StatePublished - Dec 2008

Keywords

  • 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methy l)benzamide
  • intercellular signaling peptides and proteins
  • prostate
  • prostatic neoplasms
  • transforming growth factor-β

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