Failure to Dephosphorylate Retinoblastoma Protein in Drug-resistant Cells

Hypophosphorylation of retinoblastoma protein (RB) accompanies the DNA damage-induced, p53-independent Gt 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 ceU 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.