Chemotherapeutic treatment with combinations of drugs is front-line
therapy for many types of
cancer. Combining drugs which target different signaling pathways often lessens adverse side effects while increasing the efficacy of treatment and reducing patient morbidity. A defined scheduling protocol is described by which
histone deacetylase inhibitors (HDIs) facilitate the cytotoxic effectiveness of the
topoisomerase I inhibitor camptothecin in the killing of
tumor cells. Breast and
lung cancer cell lines were treated with
camptothecin and
sodium butyrate (NaB) or
suberoylanilide hydroxamic acid on the day of, the day before, or the day after
camptothecin addition. Depending on the time of addition, NaB-treated cells displayed a spectrum of responses from protection to sensitization, indicating the critical nature of timing in the use of HDIs. The IC80 (72-hour assay) dose of 100 nmol/L
camptothecin could be lowered to 15 nmol/L
camptothecin while maintaining or surpassing cell killing of the single agent if combined with an HDI added 24 to 48 hours after
camptothecin. Experiments determined that cells arrested in G2-M by
camptothecin were most sensitive to subsequent HDI addition. Western blot analysis indicated that in
camptothecin-arrested cells, NaB decreases
cyclin B levels, as well as the levels of the antiapoptotic
proteins XIAP and
survivin. These findings suggest that reducing the levels of these critical antiapoptotic factors may increase the efficacy of
topoisomerase I inhibitors in the clinical setting if given in a sequence that does not prevent or inhibit
tumor cell progression through the S phase.