phenanthrenes and Esophageal-Neoplasms

Triptolide, the component of traditional Chinese herb, has been used as an inflammatory medicine and reported to be anti-tumor for various cancers recently. However, the effect of triptolide on Esophageal Squamous Cell Cancer (ESCC) has not yet been elucidated. In the study, we found that triptolide significantly inhibited cell proliferation, invasion, migration and survivability of ESCC cells. Moreover, we observed that triptolide induced ESCC cell cycle arrest at the G1/S phase and apoptosis through cyclin D1-CDK4/6 regulation and caspases activation. In addition, we revealed that triptolide regulates cell apoptosis and metastasis by p53 and mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, respectively. Meanwhile, the inhibitory effect of triptolide on ESCC was validated in mouse xenograft model. So, we propose that triptolide may be a candidate drug for ESCC.

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diterpenes; Epoxy Compounds; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Extracellular Signal-Regulated MAP Kinases; Humans; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Phenanthrenes; Xenograft Model Antitumor Assays

Previous epidemiological and laboratory studies have indicated an association between the ingestion of opium pyrolysates, dietary deficiencies and the high incidence of oesophageal cancer in subjects in north-east Iran. Pyrolysates of opium, and particularly of morphine, a major opium alkaloid, were both shown to contain similar highly mutagenic substances that were also clastogenic in mammalian cells and which transformed hamster embryo cells in culture. We now report the isolation and characterization of nine of the most abundant mutagenic compounds present in morphine pyrolysates, using h.p.l.c, GC-MS and n.m.r. spectroscopy. The hitherto unknown compounds, all containing a hydroxyphenanthrene moiety, were identified as: I, 3-methyl-3H-naphth[1,2-e]indol-10-ol; II, 1,2-dihydro-3-methyl-3H-naphth[1,2-e]indol-10-ol; III, 1-methyl-1H-naphth[2,1-g]indol-10-ol; IV, 2-methylphenanthro[3,4-d]-[1,3]oxazol-10-ol; V, 6-methylaminophenanthren-3-ol; VI, 2-methyl-3H-phenanthro[3,4-d]imidazol-10-ol; VII, 1,2-dimethyl-1H-phenanthro[3,4-d]imidazol-10-ol; VIII, 2,5-dimethyl-3H-phenanthro[3,4-d]imidazol-10-ol; and IX, 2-ethyl-3H-phenanthro[3,4-d]imidazol-10-ol. Structures for the heterocyclic rings of compounds IV and VI to IX are tentative. Mutagenicity in Salmonella typhimurium TA98 in the presence of rat liver homogenates increased in the order listed and ranged over four orders of magnitude, IX being 1000 times more active than benzo[a]pyrene. Compounds I and VII were converted by rat liver 9000 g supernatant into phenols and dihydrodiols, implicating arene oxides as ultimate mutagens. The formation and reaction of these arene oxides was shown by trapping experiments in vitro with ethanethiol and subsequent characterization of the ethyl sulfide reaction products. The order of biological activity of compounds I-IX, dependent on the structure of the heterocyclic ring, suggests that carbocations, resonance-stabilized as quinone methides, are their ultimate reactive metabolites. Our results lend additional support to the role of opium pyrolysates as an etiological factor in oesophageal cancer in north-east Iran.

Topics: Biotransformation; Chromatography, High Pressure Liquid; Deficiency Diseases; Esophageal Neoplasms; Gas Chromatography-Mass Spectrometry; Hot Temperature; Humans; Hydroxylation; Iran; Magnetic Resonance Spectroscopy; Morphine; Mutagenicity Tests; Mutagens; Opium; Phenanthrenes; Structure-Activity Relationship