Epimedokoreanin C, A Prenylated Flavonoid Isolated From Epimedium Koreanum, Induces Non-Apoptotic Cell Death With The Characteristics Of Methuosis In Lung Cancer Cells

Methuosis is a novel type of non-apoptotic cell death characterized by accumulation of cytoplasmic vacuoles. Identification of molecules that induce methuosis may provide alternative therapeutics for cancers that are refractory to apoptosis. Epimedokoreanin C (EKC) is a prenylated flavonoid isolated from a Chinese herb Epimedium koreanum. In this article, we described that EKC reduced cell viability accompanied by extreme vacuolation in human lung cancer cells. The EKC-induced cell death was clarified as non-apoptosis based on the absence of apoptotic changes. The vacuoles stimulated by EKC were supposed to be derived from macropinocytosis based on the engulfment of extracellular fluid tracer, Lucifer Yellow. The vacuoles acquired some characteristics of late endosomes supported that EKC-induced cell death could be described as methuosis. Rac1 and Arf6 were found to be regulated inversely after EKC treatment. Blocking Rac1 activation with the specific Rac1 inhibitor EHT 1864 prevented the accumulation of vacuoles induced by EKC markedly, suggested that the regulation of Rac1 and Arf6 was at least partial mechanism involved in EKC induced methuosis. EKC synergized the effects of doxorubicin and etoposide, demonstrating the effectiveness of using EKC to synergize conventional chemotherapy. Collectively, EKC was demonstrated as a methuosis-like cell death inducer in lung cancer NCI-H292 and A549 cells. It has the potential to be used as an attractive prototype for developing drugs that could kill apoptosis-resistant cancer cells.