4-Nerolidylcatechol analogues as promising anticancer agents

Abstract

4-Nerolidylcatechol (1) is an isolated compound from Pothomorphe umbellata L. (Piperaceae) with promising antitumor cells properties. However it presents lability under light and room temperatures. Many efforts have been directed towards discovering anticancer agents endowed with cytotoxic activities. Here, we evaluated cytotoxic effects of 4-NRC analogues (LQFMs 2-6) and the cell death pathways induced by these compounds in multidrug-resistant K562 cells. Compounds (2-6) exhibited cytotoxic activities in a concentration-dependent manner against leukaemic cells, specially the compounds (3) and (5). Additionally, compounds (1), (3) and (5) promoted marked alterations on the cell morphology, including nuclear changes as demonstrated by Hoescht 33342 staining. Moreover, these compounds promoted apoptosis induction in K562 cells by phosphatidylserine exposure, increase of sub-G1 cells and modulation of the caspases-3/7, -8 and -9 activation. In addition, the pancaspase inhibitor z-VAD-fmk partially reduced the apoptosis induced by the compounds (1) and (5)-induced, suggesting caspase-dependent and caspase-independent cell death pathways. Compounds (1) and (5) also modified the cell cycle progression by G0/G1 and S arrest, respectively. Furthermore, compounds (1), (3) and (5) promoted mitochondrial dysfunction associated to accumulation of cytosolic cytochrome c and modulated the NF-ĸB activation. In addition, unlike their analogues, 4-NRC (1) also promoted a significant cyclin D1 inhibition. Together, these data suggest that the mechanism of cell death of 4-NRC and its analogues (3) and (5) occurs by apoptosis through mitochondrial mechanisms. Considering that LQFMs are biocompatible synthetic analogues produced by molecular simplification of (1) without the chiral centre, which is associated with the instability found in compound (1), we suggest that these compounds are promising candidates for further pre-clinical studies.

4-Nerolidylcatechol: apoptosis by mitochondrial mechanisms with reduction in cyclin D1 at G0/G1 stage of the chronic myelogenous K562 cell line

“…Flow cytometry and western blot analysis were performed for the detection of the expression level of cyclin D1 protein in K562 cells, based on the protocols described by Cortez et al. ( 2015 ) and Mota et al. ( 2016 ), respectively.…”

“… 2013 ; Cortez et al. 2015 ). In terms of anticancer properties, it has been shown that apoptosis is the main cell death type triggered by 4-NRC (Brohem et al.…”

Monografias de Plantas Medicinais Brasileiras e Aclimatadas: Volume II

“…O 4-nerolidilcatecol revelou-se citotóxico a várias linhagens de células de melanoma (IC 50 20-40μmol) e também em fibroblastos humanos (IC 50 = 50μmol), fato associado à sua capacidade de induzir a apoptose. O mecanismo nos melanomas foi atribuído à inibição do ciclo celular G1 e da atividade de MMP-2 (Brohem et al, 2009;Cortez et al, 2015). Em P. peltatum, foi demonstrado que a atividade de 4-nerolidilcatecol, quando isolado, é bem menor do que a dos extratos (Pinto et al, 2006).…”

Piper peltatum, P. umbellatum

“…O 4-nerolidilcatecol revelou-se citotóxico a várias linhagens de células de melanoma (IC 50 20-40μmol) e também em fibroblastos humanos (IC 50 = 50μmol), fato associado à sua capacidade de induzir a apoptose. O mecanismo nos melanomas foi atribuído à inibição do ciclo celular G1 e da atividade de MMP-2 (Brohem et al, 2009;Cortez et al, 2015). Em P. peltatum, foi demonstrado que a atividade de 4-nerolidilcatecol, quando isolado, é bem menor do que a dos extratos (Pinto et al, 2006).…”