Protein tyrosine phosphatase activities are involved in apoptotic cancer cell death induced by GL331, a new homolog of etoposide.
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.
Huang
T S
TS
National Health Research Institutes and Cooperative Clinical Research Laboratory at VGH-Taipei, Taiwan, ROC. tshuang@gate.sinica.edu.tw
Shu
C H
CH
Shih
Y L
YL
Huang
H C
HC
Su
Y C
YC
Chao
Y
Y
Yang
W K
WK
Whang-Peng
J
J
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
D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D011034:Podophyllotoxin