THE EFFECTS OF VINBLASTINE ON THE EXPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 LONG TERMINAL REPEAT

Previous work by our group has demonstrated induction of the HIV-LTR f ollowing exposure of cells to various DNA-damaging agents such as ultr aviolet (UV) light, cisplatin, and doxorubicin. The current experiment s were designed to determine the relative effects of the anti-mitotic drug vinblastine on expression of the HIV-LTR. Using human cervical ca rcinoma (HeLa) cells stably transfected with the chloramphenicol acety l transferase (CAT) reporter transcriptionally driven by the HIV-LTR p romoter, we demonstrated a 9-10-fold induction at 48-72 h following vi nblastine treatment. Previous experiments had demonstrated repression of cisplatin or doxorubicin-mediated HIV induction by treatment with s alicylic acid. The vinblastine induction also was repressed by salicyl ic acid treatment, but not by treatment with indomethacin, suggesting a role for the NFkB pathway in the inductive response. When UV exposur e was coupled to the vinblastine treatment, there was no additive or s ynergistic effect evident, suggesting similar paths of induction betwe en the two agents. Northern blots demonstrated that these agents were operating at the level of transcription and that salicylic acid inhibi ted vinblastine-mediated induction of HIV-LTR-CAT mRNA only if adminis tered at the same time as vinblastine; addition of salicylic acid 2 h later had no effect on transcript accumulation. All combinations of tr eatments with vinblastine and/or salicylic acid markedly reduced cell survival. (C) 1997 Elsevier Science Ltd.