Failure to dephosphorylate retinoblastoma protein in drug-resistant cells.
Hypophosphorylation of retinoblastoma protein (RB) accompanies the DNA damage-induced, p53-independent G1 arrest and apoptosis in two p53-null human leukemic cell lines, HL-60 and U937 (Q.P. Dou et al., Proc. Natl. Acad. Sci. USA, 92: 9019-9023, 1995). When an HL-60 cell line resistant to cytosine arabinoside was exposed to this DNA-damaging agent, neither RB hypophosphorylation nor apoptosis were observed. In contrast, treatment of these cells with another DNA-damaging agent, etoposide, dramatically induced these events, which were inhibitable by the addition of zinc chloride, a protein tyrosine phosphatase inhibitor. Induction of hypophosphorylation of RB may be an important novel strategy for treating drug-resistant cancers.
Dou
Q P
QP
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15213-2582, USA.
Lui
V W
VW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008387:Marine Toxins; D010080:Oxazoles / Q000494:pharmacology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D017967:Zinc Compounds / Q000494:pharmacology
D000970:Antineoplastic Agents; D002712:Chlorides; D008387:Marine Toxins; D010080:Oxazoles; D016160:Retinoblastoma Protein; D017967:Zinc Compounds; D003561:Cytarabine; D005047:Etoposide; C059041:calyculin A; C016837:zinc chloride