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.
Highlights
IntroductionConventional chemotherapeutic regimens target lung cancer cells and normal proliferating cells
Lung cancer is the leading cause of cancer-related mortality worldwide [1,2]
We identified a low molecular weight compound that suppressed endogenous MDK expression. iMDK inhibited the growth of MDK-expressing H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells in vitro
Summary
Conventional chemotherapeutic regimens target lung cancer cells and normal proliferating cells. Survival following conventional chemotherapy of lung adenocarcinoma (the most frequent type of lung cancer) provides less than one-year median survival from the time of diagnosis [3]. Molecular pathway-specific therapies for lung adenocarcinoma, e.g., targeting mutant EGFR or ALK fusions, limit non-tumor toxicity and extend survival time compared to the conventional chemotherapies [4,5,6]. There is no molecularly targeted therapy for mutant KRAS-driven lung adenocarcinoma, the most frequent type of lung adenocarcinoma in the Caucasian population. Effective molecularly targeted therapies have been developed for adenocarcinomas but not squamous cell carcinomas. Specific therapies that target various lung tumor types are desperately needed [7,8,9]
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