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Involvement of protein tyrosine phosphorylation and reduction of cellular sulfhydryl groups in cell death induced by 1' -acetoxychavicol acetate in Ehrlich ascites tumor cells.

Abstract
Elucidation of the mechanisms underlying potential anticancer drugs continues and unraveling these mechanisms would not only provide a conceptual framework for drug design but also promote use of natural products for chemotherapy. To further evaluate the efficacy of the anticancer activity of 1'-acetoxychavicol acetate (ACA), this study investigates the underlying mechanisms by which ACA induces death of Ehrlich ascites tumor cells. ACA treatment induced loss of cell viability, and Western blotting analysis revealed that the compound stimulated tyrosine phosphorylation of several proteins with 27 and 70 kDa proteins being regulated in both dose- and time-dependent manner prior to loss of viability. Protein tyrosine kinase inhibitor herbimycin A moderately protected cells from ACA-induced toxicity. In addition, cellular glutathione and protein sulfydryl groups were also significantly reduced both dose- and time-dependently during evidence of cell death. Replenishing thiol levels by antioxidant, N-acetylcysteine (NAC), an excellent supplier of glutathione and precursor of glutathione, substantially recovered the viability loss, but the recovery being time-dependent, as late addition of NAC (at least 30 min after ACA addition to cultures) was, however, ineffective. Addition of NAC to ACA treated cultures also abolished tyrosine phosphorylation of the 27 kDa protein. These results, at least partly, identify cellular sulfhydryl groups and protein tyrosine phosphorylation as targets of ACA cytotoxicity in tumor cells.
AuthorsJerry Moffatt, David Opare Kennedy, Akiko Kojima, Tadayoshi Hasuma, Yoshihisa Yano, Shuzo Otani, Akira Murakami, Koichi Koshimizu, Hajime Ohigashi, Isao Matsui-Yuasa
JournalChemico-biological interactions (Chem Biol Interact) Vol. 139 Issue 2 Pg. 215-30 (Feb 20 2002) ISSN: 0009-2797 [Print] Ireland
PMID11823008 (Publication Type: Journal Article)
Chemical References
  • Anticarcinogenic Agents
  • Benzoquinones
  • Benzyl Alcohols
  • Enzyme Inhibitors
  • Lactams, Macrocyclic
  • Quinones
  • Sulfhydryl Compounds
  • Terpenes
  • Rifabutin
  • Tyrosine
  • 1'-acetoxychavicol acetate
  • herbimycin
  • Glutathione
Topics
  • Animals
  • Anticarcinogenic Agents (pharmacology)
  • Benzoquinones
  • Benzyl Alcohols
  • Blotting, Western
  • Carcinoma, Ehrlich Tumor (drug therapy, metabolism, pathology)
  • Cell Survival (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors (pharmacology)
  • Glutathione (metabolism)
  • Lactams, Macrocyclic
  • Oxidation-Reduction
  • Phosphorylation
  • Quinones (pharmacology)
  • Rifabutin (analogs & derivatives)
  • Sulfhydryl Compounds (metabolism)
  • Terpenes (pharmacology)
  • Time Factors
  • Tumor Cells, Cultured (drug effects)
  • Tyrosine (metabolism)

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