Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer

PLoS One. 2013 Aug 16;8(8):e71093. doi: 10.1371/journal.pone.0071093. eCollection 2013.

Abstract

Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Coumarins / pharmacology*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Midkine
  • Molecular Weight
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Nerve Growth Factors / antagonists & inhibitors*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Thiazoles / pharmacology*
  • Tumor Burden / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • 3-(2-(4-fluorobenzyl)imidazo(2,1-beta)(1),(3)thiazol-6-yl)-2H-chromen-2-one
  • Antineoplastic Agents
  • Carrier Proteins
  • Coumarins
  • Cytokines
  • MDK protein, human
  • Nerve Growth Factors
  • RNA, Small Interfering
  • Thiazoles
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • pleiotrophin
  • Midkine
  • Phosphatidylinositol 3-Kinases