Novel derivative of benzofuran induces cell death mostly by G2/M cell cycle arrest through p53-dependent pathway but partially by inhibition of NF-kappaB.

The Dracaena resin is widely used in traditional medicine as an anticancer agent, and benzofuran lignan is the active component. In this report, we provide evidence that the synthetic derivative of benzofuran lignan (Benfur) showed antitumor activities. It induced apoptosis in p53-positive cells. Though it inhibited endotoxin-induced nuclear factor kappaB (NF-kappaB) activation in both p53-positive and -negative cells, the activation of caspase 3 was observed in p53-positive cells. It showed partial cell death effect in both p53-positive and -negative cells through inhibition of NF-kappaB. Cell cycle analysis using flow cytometry showed that treatment with this novel benozofuran lignan derivative to Jurkat T-cells, but not U-937 cells, resulted in a G2/M arrest in a dose- and time-dependent manner. It increased amounts of p21, p27, and cyclin B, but not phospho-Rb through p53 nuclear translocation in Jurkat T-cells, but not in U-937 cells. It inhibited amounts of MDM2 (murine double minute 2) by repressing the transcription factor Sp1, which was also proved in silico. It induced cell death in tumor cells, but not in primary T-cells. Overall, our data suggest that Benfur-mediated cell death is partially dependent upon NF-kappaB, but predominantly dependent on p53. Thus, this novel benzofuran lignan derivative can be effective chemopreventive or chemotherapeutic agent against malignant T-cells.

Novel caffeic acid ester derivative induces apoptosis by expressing FasL and downregulating NF-KappaB: Potentiation of cell death mediated by chemotherapeutic agents.

In the present study, we demonstrate the biological activity of esterified caffeic acid with methyl vanillate also termed as caffeic acid methyl vanillate ester (CAMVE). CAMVE potentiates TNF-induced cell death as analyzed by cell viability assay and blocks inflammatory stimuli-induced nuclear transcription factor kappaB (NF-kappaB) activation and NF-kappaB-dependent genes expression. CAMVE-mediated inhibition of NF-kappaB or induction of cell death is not cell type specific. CAMVE inhibits cell proliferation by inhibiting G1 to S phase progression. It suppresses TNF-induced Bcl-2 expression and potentiates chemotherapeutic agents-mediated cell death. CAMVE enhances intracellular free Ca(2+) and thereby activates calcineurin. Calcineurin, in turns, activates nuclear transcription factor NF-AT and its dependent genes such as FasL, which induces cell death. The data demonstrate that CAMVE is one of the combinatorial products, which is able to inhibit NF-kappaB regulated genes and cell proliferation. The combinatorial synthesis of novel caffeic ester derivatives can be a useful approach to generate potent chemotherapeutic agents and designing CAMVE as potent therapeutic agent for combination therapy may be useful to treat tumors.

Downregulation of inflammatory responses by novel caffeic acid ester derivative by inhibiting NF-kappa B.

INTRODUCTION: Considering anti-tumorigenic activity of caffeic acid phenyl ester, synthesis of several esterified form of caffeic acid is a novel approach in designing for potent drugs. RESULTS: Our study demonstrates that esterified caffeic acid with methyl vanillate, termed as caffeic acid methyl vanillate ester (CAMVE), blocked inflammatory stimuli-induced inflammatory responses. It decreased amounts of iNOS, Cox-2, and ICAM1 by inhibiting NF-kappaB through inhibition of IKK activity, I kappaB alpha degradation, and p65 nuclear translocation. CONCLUSION: Overall, our data suggest that novel caffeic acid ester down-regulates inflammatory responses through inhibition of NF-kappaB and dependent several gene expressions, further suggesting its efficacy as a promising therapeutic agent.

A dihydrobenzofuran lignan induces cell death by modulating mitochondrial pathway and G2/M cell cycle arrest.

A dihydrobenzofuran lignan, the dimerization product of caffeic acid methyl ester, has shown pronounced antileishmanial and antiplasmodial activities. The present study showed the effect of this compound on cell cycle and apoptosis. Flow cytometric analysis revealed that the cells were arrested in the G2/M phase. Activation of caspase 3, but not caspase 8, generation of ROS, upstream of caspase-3, release of cytochrome c,increase in Bax level, and decrease in Bcl-2 level suggested the involvement of mitochondrial damage. Loss of mitochondrial transmembrane potential independent of caspase activation further suggested the mode of apoptosis. Dihydrobenzofuran-mediated cell death was absent in Bcl-xL-overexpressed cells. Overall, our results justify the role of dihydrobenzofuran lignan as potential antitumor agent, causing G2/M arrest and apoptosis involving the mitochondrial controlled pathway. These findings open promising insights as to how this specific dihydrobenzofuran lignan mediates cytotoxicity and may prove a molecular rationale for future therapeutic interventions in carcinogenesis.