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.

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

“…Though iMDK alone did not inhibit cell viability of A549 cells, the combinatorial treatment of iMDK with PD0325901 significantly inhibited that of A549 cells compared to the single treatment of PD0325901. As shown previously [17], MDK is expressed in H441, H2009 and H520 cells but not in A549 cells. These results indicate that the combinatorial treatment inhibits cell viability of NSCLC cells independently of KRAS mutations or MDK expression.…”

“…For example, a PI3K inhibitor PI-103 inhibited the PI3K pathway while activating the MAPK pathway [16], suggesting a potential mechanism for tumor survival by the compensatory activation of an alternative tumorigenic pathway. We recently reported a novel PI3K inhibitor iMDK, which was originally identified as a small molecule inhibiting the growth factor MDK (also known as midkine or MK) [17]. While its direct targets are unknown, iMDK inhibited phosphorylation of PI3K and AKT, indicating that iMDK serves as a PI3K inhibitor [17].…”

“…We recently reported a novel PI3K inhibitor iMDK, which was originally identified as a small molecule inhibiting the growth factor MDK (also known as midkine or MK) [17]. While its direct targets are unknown, iMDK inhibited phosphorylation of PI3K and AKT, indicating that iMDK serves as a PI3K inhibitor [17]. Similarly to PI-103 [16], iMDK activated phosphorylation of ERK and P38MAPK while inhibiting the PI3K pathway [17].…”

“…While its direct targets are unknown, iMDK inhibited phosphorylation of PI3K and AKT, indicating that iMDK serves as a PI3K inhibitor [17]. Similarly to PI-103 [16], iMDK activated phosphorylation of ERK and P38MAPK while inhibiting the PI3K pathway [17]. Since the combined inhibition of the PI3K and MAPK pathways by PI-103 and a MAPK inhibitor PD0325901 enhanced cell killing of NSCLC [16], in the present study, we tested whether the novel PI3K inhibitor iMDK further enhanced cell death of NSCLC in the presence of PD0325901.…”

DcR3, TFF3, and Midkine Are Novel Serum Biomarkers in Small Intestinal Neuroendocrine Tumors

“…Midkine also has predictive ability regarding the response to adjuvant chemotherapy in multiple cancers [43,44] . Several successful attempts have been made at trying to develop novel cancer treatments targeting the midkine gene in tumors overexpressing midkine, with methods including molecular engineering [45][46][47][48][49][50][51] . This study revealed that all SI-NETs analyzed expressed midkine, and that targeting this gene might potentially result in novel treatment for SI-NET patients.…”