TY  - JOUR
AU  - Omer, Ejlal A
AU  - Zhou, Min
AU  - Roos, Wynand P
AU  - Rashan, Luay J
AU  - Fiebig, Heinz-Herbert
AU  - Klauck, Sabine
AU  - Shan, Letian
AU  - Efferth, Thomas
TI  - Oleandrin-mediated suppression of MELK induces apoptosis, autophagy, and ferroptosis in human non-small cell lung cancer cells.
JO  - Phytomedicine
VL  - 147
SN  - 0944-7113
CY  - München [u.a.]
PB  - Elsevier
M1  - DKFZ-2025-01956
SP  - 157173
PY  - 2025
AB  - 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).To explore the potential therapeutic value of oleandrin against different cancer types with emphasis on NSCLC.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.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.Oleandrin could potentially have therapeutic effects for NSCLC patients and possibly for other cancer types.
KW  - Humans
KW  - Cardenolides: pharmacology
KW  - Carcinoma, Non-Small-Cell Lung: drug therapy
KW  - Animals
KW  - Apoptosis: drug effects
KW  - Zebrafish
KW  - Lung Neoplasms: drug therapy
KW  - Autophagy: drug effects
KW  - Ferroptosis: drug effects
KW  - A549 Cells
KW  - Cell Movement: drug effects
KW  - Cell Line, Tumor
KW  - Antineoplastic Agents, Phytogenic: pharmacology
KW  - Xenograft Model Antitumor Assays
KW  - Nerium: chemistry
KW  - Cardiac glycosides (Other)
KW  - In vivo (Other)
KW  - NSCLC (Other)
KW  - Natural products (Other)
KW  - Nerium oleander (Other)
KW  - Phytotherapy (Other)
KW  - Programmed cell death (Other)
KW  - Cardenolides (NLM Chemicals)
KW  - oleandrin (NLM Chemicals)
KW  - Antineoplastic Agents, Phytogenic (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40916237
DO  - DOI:10.1016/j.phymed.2025.157173
UR  - https://inrepo02.dkfz.de/record/304880
ER  -