title: Protein tyrosine phosphatase activities are involved in apoptotic cancer cell death induced by GL331, a new homolog of etoposide.
abstract: GL331 is a semisynthetic topoisomerase II inhibitor derived from a plant toxin podophyllotoxin. In 72-h exposure assays, LD50 values of GL331 range from 0.5 to 2 microM, which are three- to ten-fold lower than those of its homologous compound etoposide (VP-16), depending on different cancer cell lines including nasopharyngeal, hepatocellular, gastric, cervical and colon cancer types. Apoptotic DNA ladders could be detected when cancer cells were treated with GL331 for 24 h even if the Bcl-2 and Bax protein levels were not altered during the period. Besides acting as topoisomerase II inhibitors, both GL331 and VP-16 decrease the cellular protein tyrosine kinase (PTK) activities in cancer cells. The activities of protein tyrosine phosphatase (PTP) are significantly increased after GL331 treatment but are not affected by VP-16. GL331-induced internucleosomal cleavage can be efficiently prevented by two inhibitors of PTP, sodium orthovanadate and zinc chloride, but not by okadaic acid, which inhibits serine/threonine phosphatase activity. These results indicate that GL331 may induce apoptotic cell death, and that activation of protein tyrosine phosphatases may be involved in this process.
authors.affiliation: National Health Research Institutes and Cooperative Clinical Research Laboratory at VGH-Taipei, Taiwan, ROC. tshuang@gate.sinica.edu.tw
authors.forename: T S
authors.initials: TS
authors.lastname: Huang
authors.forename: C H
authors.initials: CH
authors.lastname: Shu
authors.forename: Y L
authors.initials: YL
authors.lastname: Shih
authors.forename: H C
authors.initials: HC
authors.lastname: Huang
authors.forename: Y C
authors.initials: YC
authors.lastname: Su
authors.forename: Y
authors.initials: Y
authors.lastname: Chao
authors.forename: W K
authors.initials: WK
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Whang-Peng
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology*; D007928:Lethal Dose 50; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D011034:Podophyllotoxin