Honokiol induces paraptosis and apoptosis and exhibits schedule-dependent synergy in combination with imatinib in human leukemia cells

Abstract

Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, has been shown to inhibit growth and induce apoptosis in different cancer cell lines. This study shows that honokiol can induce a cell death distinct from apoptosis at lower concentrations. The death was characterized by cytoplasmic vacuolization with the endoplasmic reticulum swelling and accompanied by apoptosis at higher concentrations in NB4 and K562 cells. The two death processes may be in sequence at lower concentrations and in parallel with the increase of honokiol concentration. Membrane-associated cytotoxicity was involved in honokiol-induced paraptosis and apoptosis. Furthermore, honokiol inhibited concentration-dependent cell adhesion to extracellular matrix for NB4 cells. In addition, the cytotoxicity of honokiol combined treatment with imatinib was schedule- and concentration-dependent and the sequential administration of honokiol before imatinib appeared to be more beneficial in K562 cells. Taken together, the data suggest that honokiol induced a novel cell death pathway and there was cross-talk between apoptotic and non-apoptotic programmed cell death caused by honokiol in leukemia cells. Moreover, honikiol exhibited schedule-dependent synergy in combination with imatinib and sequential administration of imatinib followed by honokiol could be the optimal sequence to combine these two drugs in K562 cells.

Zuo Jin Wan, a Traditional Chinese Herbal Formula, Reverses P-gp-Mediated MDRIn VitroandIn Vivo

“…In our study, we found ZJW had the synergistic effect in chemotherapeutic drugs induced-cell apoptosis in a time-dependent manner, as several previous reports also have shown the synergy effect of traditional Chinese prescriptions and formulae [30, 31]. However, we did not observe obvious alterations in any cell cycle arrest of HCT-116/L-OHP cells after treatment with the formula.…”

Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines

“…Functional annotation confirmed results from previous studies that identified kinase binding, apoptosis and vacuole/lysosome related genes as targets of imatinib treatment [37,38]. It is noteworthy that a recent genome-wide association study in yeast identified the vacuolar proton transporter ATPase (V-ATPase) protein, which maintains vacuolar pH, as an important target of imatinib action [39].…”

Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking

“…The remarkable collateral sensitivity of honokiol in EGFRexpressing, otherwise drug-resistant U87.MG EGFR cells may open the possibility that combination treatments of established anticancer drugs together with honokiol may result in synergistic tumor cell killing, Indeed, this has been repeatedly reported for several anticancer drugs as well as for radiotherapy (Hu et al, 2008;Jiang et al, 2008;Leeman-Neill et al, 2010;Wang et al, 2010;Arora et al, 2011;Cheng et al, 2011;He et al, 2011;Tian et al, 2013). If one imagines that honokiol would find its way into the clinics, it can be expected that this compound will be rather used as part of a combination therapy than as monotherapy.…”