Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer

Huifang Hao, Yutaka Maeda, Takuya Fukazawa, Tomoki Yamatsuji, Munenori Takaoka, Xiao Hong Bao, Junji Matsuoka, Tatsuo Okui, Tsuyoshi Shimo, Nagio Takigawa, Yasuko Tomono, Motowo Nakajima, Iris M. Fink-Baldauf, Sandra Nelson, William Seibel, Ruben Papoian, Jeffrey A. Whitsett, Yoshio Naomoto

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27 Citations (Scopus)

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.

Original languageEnglish
Article numbere71093
JournalPloS one
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 16 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hao, H., Maeda, Y., Fukazawa, T., Yamatsuji, T., Takaoka, M., Bao, X. H., Matsuoka, J., Okui, T., Shimo, T., Takigawa, N., Tomono, Y., Nakajima, M., Fink-Baldauf, I. M., Nelson, S., Seibel, W., Papoian, R., Whitsett, J. A., & Naomoto, Y. (2013). Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer. PloS one, 8(8), [e71093]. https://doi.org/10.1371/journal.pone.0071093