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  3. A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor

A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor

  • Exp Cell Res. 2015 Jul 15;335(2):197-206. doi: 10.1016/j.yexcr.2015.03.019.
Naomasa Ishida 1,  Takuya Fukazawa 2,  Yutaka Maeda 3,  Tomoki Yamatsuji 1,  Katsuya Kato 4,  Kenichi Matsumoto 5,  Tsuyoshi Shimo 5,  Nagio Takigawa 6,  Jeffrey A Whitsett 3,  Yoshio Naomoto 1
Affiliations

Affiliations

  • 1 Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan.
  • 2 Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan. Electronic address: FukazawaT@aol.com.
  • 3 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229-3039, United States.
  • 4 Department of Diagnostic Radiology 2, Kawasaki Medical School, Okayama 700-8505, Japan.
  • 5 Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
  • 6 Department of General Internal Medicine 4, Kawasaki Medical School, Okayama 700-8505, Japan.
PMID: 25839409 DOI: 10.1016/j.yexcr.2015.03.019
Abstract

The PI3K-AKT pathway is expected to be a therapeutic target for non-small cell lung Cancer (NSCLC) treatment. We previously reported that a novel PI3K Inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing Apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung Cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.

Keywords

MEK; NSCLC; PI3K.

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