Abstract
BackgroundPlant derived compounds have been shown to be important sources of several anti-cancer agents. As cell cycle deregulation and tumor growth are intimately linked, the discovery of new substances targeting events in this biochemical pathway would be of great value. The anti-leukemic effect of an ethanolic extract of Pterodon pubescens seeds (EEPp) has been previously demonstrated and now we show that a terpenic subfraction (SF5) of EEPp containing farnesol, geranylgeraniol and vouacapan derivatives induces apoptosis in the human chronic myelogenous leukemia cell line K562. This work addresses SF5’s antiproliferative mechanisms in these cells since they are still unclear.MethodsDNA synthesis in K562 cells was assessed by [3H]-methyl-thymidine incorporation and cell cycle status by flow cytometry. The expression of cyclins D1 and E2, of the cell cycle inhibitor p21 and of the proto-oncogene c-myc was evaluated by semi-quantitative RT-PCR. Extracellular-signal-regulated kinases (ERK) 1/2 and nuclear factor kappa B (NF-κB) activation was evaluated by western blotting.ResultsIn K562 cells, SF5 treatment induced a higher inhibition of DNA synthesis and cell growth than the original EEPp hexanic fraction from which SF5 originated, and also arrested the cell cycle in G1. Exposure of these cells to SF5 led to a decrease in cyclin E2 and c-myc expression while p21 mRNA levels were increased. Furthermore, SF5 inhibited the activation of mitogen-activated protein kinase (MAPK) ERK 1/2 and NF-κB.ConclusionsThis work suggests that the anti-leukemic action of SF5 is linked to the inhibition of ERKs, NF-κB and c-myc signaling pathways resulting in reduced cyclin E2 mRNA expression and cell cycle arrest in the G1 phase.
Highlights
Plant derived compounds have been shown to be important sources of several anti-cancer agents
Effects of SF5 on leukemic cell growth hexanic fraction of EEPp (HEX) subfractionation of ethanolic extract of Pterodon pubescens seeds (EEPp) resulted in a subfraction (SF5) with greater inhibitory effect on cell growth
Effects of SF5 on DNA synthesis and on the cell cycle Since SF5 treatment inhibited the growth of K562 leukemic cells, its effect on DNA synthesis (Figure 2A) and on the cell cycle (Figure 2B) was analyzed
Summary
Plant derived compounds have been shown to be important sources of several anti-cancer agents. As cell cycle deregulation and tumor growth are intimately linked, the discovery of new substances targeting events in this biochemical pathway would be of great value. As cell cycle deregulation and tumor growth are intimately linked [1,2], the discovery of new substances targeting events in this biochemical pathway would be of great. One of them is the MAPK pathway, which is formed by a cascade of kinases, generally referred to as Raf/MEK/ ERK In this pathway, activated extracellular signalregulated kinases (ERKs) translocate into the nucleus and regulate the activity of transcription factors such as c-myc and others [4,5], resulting in the expression of genes required for cell cycle progression like cyclins D1 and E and p27 [6,7]. The expression of these cyclins and of other cell cycle related genes is stimulated by the NF-κB transcription factor [8,9] which influences the epigenetic regulation of gene transcription by increasing, for example, the expression of O6-methylguanine DNA methyltransferase, an important DNA damage repair enzyme [10]
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