Pharmacological induction of leukotriene B4-12-hydroxydehydrogenase suppresses the oncogenic transformation of human hepatoma HepG2 cells

Abstract

Abstract. Leukotriene B4-12-hydroxydehydrogenase (LTB4DH) is characterized as a chemopreventive and tumor suppressor gene. The aim of this study was to investigate the pharmacological induction of LTB4DH and potential anticancer activity. Using HepG2 cells as a cellular detector, we successfully isolated the active compounds from the herbs Radix Astragali and Radix Paeoniae Rubra through a bioactivity-guided fractionation procedure. Using various analytical techniques including electronic spray ionization-mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR), gallic acid (GA) was identified as the active compound from Radix Paeoniae Rubra whereas the active compound from Radix Astragali, designated as RA-C, was also purified to the extent that it is now suitable for further identifi cation. We found that the active compounds from these two different herbs synergistically induced LTB4DH expression in a dose-and time-dependent manner. A key finding was that commercial GA in combination with purified RA-C attenuated the focus formation and anchorage-independent growth, two indexes of in vitro oncogenic transformation, of HepG2 cells via the induction of LTB4DH expression. Moreover, the combination of GA and purified RA-C significantly induced G2/M cell cycle arrest in HepG2 cells. Our results demon strated for the first time that GA and purified RA-C suppress the in vitro oncogenic transformation of HepG2 cells via the induction of LTB4DH expression. Importantly, pharmaco logical induction of LTB4DH represents a potential alternative strategy for the therapy of hepatocellular carcinoma.

An Enzyme That Inactivates the Inflammatory Mediator Leukotriene B4 Restricts Mycobacterial Infection

“…LTB 4 -mediated inflammation may have relevance to oncogenic transformation, as LTB 4 and components of its synthetic pathway are induced in different cancers [23]–[25]. Particularly intriguing from a therapeutic perspective is the ability of gallic acid and a purified compound from Radix astragali to induce LTB4DH expression and limit oncogenic transformation [26]. Specific pharmacological inducers of LTB4DH expression, besides serving as novel anti-inflammatory therapies, may provide a new route to addressing the known hypersusceptibility to tuberculosis of individuals with high LTA4H expression [2].…”

Plant Natural Products Calycosin and Gallic Acid Synergistically Attenuate Neutrophil Infiltration and Subsequent Injury in Isoproterenol-Induced Myocardial Infarction: A Possible Role for Leukotriene B4 12-Hydroxydehydrogenase?

“…Therefore, we developed a bias-free genome-wide biological response fingerprinting (BioReF) approach for the identification of target genes from the entire cellular genes in response to the complex mixture of plant natural products [ 23 ]. Thus, the target genes selected by BioReF may be responsive to two or multidrugs [ 24 ]. As a proof of principle, we previously identified LTB4DH as target gene for a well-documented poststroke rehabilitation formulation ISF-1 [ 23 ].…”

Bioactivity-Guided Fractionation Identifies Amygdalin as a Potent Neurotrophic Agent from Herbal MedicineSemen PersicaeExtract

“…Compared with the single target-based bioactivity-guided fractionation, our BioReF-based strategy guarantees the high success rate for the identification of the active compounds from complex herbal medicines. For example, we have successfully identified the active compounds for inducing heme oxygenase-1 (HO-1) and leukotriene B4 12-hydroxydehydrogenase (LTB4DH) from the well-known poststroke rehabilitation formulation ISF-1 [22, 23]. In the present study, we investigated the activity of herbal medicine Semen Persicae in promoting neurite outgrowth in PC12 cells.…”