title: Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer.
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.
authors: Kawasaki Hospital Research Center, Kawasaki Medical School, Okayama, Japan.
authors: Huifang
authors: H
authors: Hao
authors: Yutaka
authors: Y
authors: Maeda
authors: Takuya
authors: T
authors: Fukazawa
authors: Tomoki
authors: T
authors: Yamatsuji
authors: Munenori
authors: M
authors: Takaoka
authors: Xiao-Hong
authors: XH
authors: Bao
authors: Junji
authors: J
authors: Matsuoka
authors: Tatsuo
authors: T
authors: Okui
authors: Tsuyoshi
authors: T
authors: Shimo
authors: Nagio
authors: N
authors: Takigawa
authors: Yasuko
authors: Y
authors: Tomono
authors: Motowo
authors: M
authors: Nakajima
authors: Iris M
authors: IM
authors: Fink-Baldauf
authors: Sandra
authors: S
authors: Nelson
authors: William
authors: W
authors: Seibel
authors: Ruben
authors: R
authors: Papoian
authors: Jeffrey A
authors: JA
authors: Whitsett
authors: Yoshio
authors: Y
authors: Naomoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D000078792:Midkine; D008970:Molecular Weight; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C587597:3-(2-(4-fluorobenzyl)imidazo(2,1-beta)(1),(3)thiazol-6-yl)-2H-chromen-2-one; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D003374:Coumarins; D016207:Cytokines; C066254:MDK protein, human; D009414:Nerve Growth Factors; D034741:RNA, Small Interfering; D013844:Thiazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C066845:pleiotrophin; D000078792:Midkine; D019869:Phosphatidylinositol 3-Kinases
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