Eupatorin-induced cell death in human leukemia cells is dependent on caspases and activates the mitogen-activated protein kinase pathway.

Sara Estévez,José Quintana,María Teresa Marrero,Francisco Estévez,Rajesh Mohanraj

doi:10.1371/journal.pone.0112536

Sara Estévez, José Quintana + Show 3 more

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https://doi.org/10.1371/journal.pone.0112536

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Journal: PloS one	Publication Date: Nov 12, 2014
Citations: 32	License type: CC BY 4.0

Affiliation: University of Las Palmas de Gran Canaria

Abstract

Eupatorin is a naturally occurring flavone that inhibits cell proliferation in human tumor cells. Here we demonstrate that eupatorin arrests cells at the G2-M phase of the cell cycle and induces apoptotic cell death involving activation of multiple caspases, mitochondrial release of cytochrome c and poly(ADP-ribose) polymerase cleavage in human leukemia cells. This flavonoid induced the phosphorylation of members of the mitogen-activated protein kinases and cell death was attenuated by inhibition of c-jun N-terminal kinases/stress activated protein kinases. Eupatorin-induced cell death is mediated by both the extrinsic and the intrinsic apoptotic pathways and through a mechanism dependent on reactive oxygen species generation.

Highlights

Flavonoids are polyphenolic compounds that display a vast array of biological activities and they are of great current interest due to their anticancer activities [1]
We examined the effect of eupatorin (Figure 1A) on the growth of three human leukemia cells and found that human myeloid (HL-60 and U937) and lymphoid (Molt-3) cell lines were highly sensitive to the anti-proliferative effect of this flavonoid
Eupatorin Induces Apoptosis in Human Leukemia Cells To study the mechanism involved in eupatorin-induced cytotoxicity, we analyzed the nuclei of treated cells using fluorescent microscopy and observed the typical morphologic characteristics of apoptotic cells such as nuclear condensation and fragmented chromatin (Figure 2A)

Summary

Introduction

Flavonoids are polyphenolic compounds that display a vast array of biological activities and they are of great current interest due to their anticancer activities [1]. The extrinsic pathway involves cell surface death receptors, such as tumor necrosis factor, Fas and TRAIL receptors, and is dependent on the initiator caspase-8 which cleaves and activates the downstream effector caspases (caspase-3, -6 and -7), inducing a cascade of caspases. The intrinsic pathway involves the activation of procaspase-9 by cytochrome c released from mitochondria, which cleaves and activates downstream effector caspases-3, -6 and -7, which in turn target key structural and regulatory proteins for proteolysis to effect cell death [5]. Both caspase-8 and caspase-9 activate caspase-3 which is responsible for breaking specific cellular proteins during apoptosis [6]

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