herbimycin and Carcinoma--Ehrlich-Tumor

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.

Topics: Animals; Anticarcinogenic Agents; Benzoquinones; Benzyl Alcohols; Blotting, Western; Carcinoma, Ehrlich Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Glutathione; Lactams, Macrocyclic; Oxidation-Reduction; Phosphorylation; Quinones; Rifabutin; Sulfhydryl Compounds; Terpenes; Time Factors; Tumor Cells, Cultured; Tyrosine

Several halogenated and other related derivatives of herbimycin A have been synthesized and evaluated in vivo for their activities against Ehrlich ascites carcinoma. Some of these derivatives show higher activities than herbimycin A. Among them the derivatives modified at the 4, 5, 6, and 7-positions of the ansa chain showed particularly high activities.

Topics: Animals; Benzoquinones; Carcinoma, Ehrlich Tumor; Halogens; Lactams, Macrocyclic; Mice; Neoplasms, Experimental; Quinones; Rifabutin; Structure-Activity Relationship

Topics: Animals; Anti-Bacterial Agents; Benzoquinones; Carcinoma, Ehrlich Tumor; Chemical Phenomena; Chemistry; HeLa Cells; Humans; Lactams, Macrocyclic; Magnetic Resonance Spectroscopy; Quinones; Rifabutin

Topics: Animals; Antibiotics, Antineoplastic; Benzoquinones; Carcinoma, Ehrlich Tumor; Lactams, Macrocyclic; Mice; Quinones; Rifabutin; Structure-Activity Relationship