Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

Cancer Lett. 2015 Nov 1;368(1):79-87. doi: 10.1016/j.canlet.2015.07.032. Epub 2015 Jul 30.

Abstract

The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.

Keywords: BMP; BMPR1a; DMH1; Ovarian cancer; Platinum resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bone Morphogenetic Protein Receptors / metabolism
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Cell Proliferation / drug effects*
  • Cisplatin / pharmacology
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Pyrazoles / pharmacology*
  • Quinolines / pharmacology*
  • Signal Transduction / drug effects*
  • Spheroids, Cellular
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Bone Morphogenetic Proteins
  • DMH1 compound
  • Pyrazoles
  • Quinolines
  • Bone Morphogenetic Protein Receptors
  • Cisplatin