A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents

Exposure of human tumor cell lines to different chemotherapeutic drugs, ion izing radiation, and differentiating agents induced morphological, enzymati c, and ploidy changes resembling replicative senescence of normal cells. Mo derate doses of doxorubicin induced this senescence-like phenotype (SLP) in 11 of 14 tested cell lines derived from different types of human solid tum ors, including all of the lines with wild-type p53 and half of p53-mutated cell lines. SLP induction seemed to be independent from mitotic cell death, the other major effect of drug treatment. Among cells that survived drug e xposure, SLP markers distinguished those cells that became terminally growt h-arrested within a small number of cell divisions from the cells that reco vered and resumed proliferation. SLP induction in breast carcinoma cells tr eated with retinoids in vitro or in vivo was found to correlate with perman ent growth inhibition under the conditions of minimal cytotoxicity, suggest ing that this response may be particularly important for the antiproliferat ive effect of differentiating agents. The senescence-like program of termin al proliferation arrest may provide an important determinant of treatment o utcome and a target for augmentation in cancer therapy.