Oleandrin-mediated suppression of MELK induces apoptosis, autophagy, and ferroptosis in human non-small cell lung cancer cells

Abstract

Background Non-small-cell lung cancer NSCLC is the major diagnosed type of lung cancers in the USA and Europe. It is generally related to poor prognosis and low rates of survival. Oleandrin is a cardiac glycoside occurring naturally in Nerium oleander (Apocynaceae). Purpose To explore the potential therapeutic value of oleandrin against different cancer types with emphasis on NSCLC. Methods The effect of oleandrin in inhibiting the growth of different cancer cells was measured. In addition, oleandrin activity in inhibiting cell migration, suppression of MELK and inducing different modes of cell deaths were investigated using in silico, in vitro, and in vivo methods. Results Oleandrin showed activity at low nanomolar level against 17 different types of cancer cells including NSCLC. Our investigations in A549 cells indicated that oleandrin is a MELK inhibitor, as it disrupted the microtubule network and inhibited migration of A549 cells. Moreover, it induced apoptosis, autophagy, and ferroptosis. Furthermore, our in vivo data revealed that oleandrin had significantly decreased tumor growth in a A549 xenograft zebrafish model in a dose-dependent manner. In silico analyses revealed that oleandrin bound to the ligand binding pocket with higher binding affinity than the known inhibitor MELK-8a. The binding was further confirmed in vitro using microscale thermophoresis. An ADMET (absorption, distribution, metabolism, excretion, toxicity) analysis, together with our in vivo toxicity studies and the previous clinical studies suggest that oleandrin has an acceptable safety profile. Conclusion Oleandrin could potentially have therapeutic effects for NSCLC patients and possibly for other cancer types.