title: An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells.
abstract: Pharmacological activation of wild-type p53 has been found to protect normal cells in culture from cytotoxicity and nuclear aberrations caused by conventional cancer therapeutics. Hence, small-molecule p53 activators could have clinical benefits as chemoprotectants for cancer patients bearing p53-mutant tumors. We have evaluated 16 p53-based cyclotherapy regimes combining p53 activators tenovin-6, leptomycin B, nutlin-3 and low dose actinomycin D, with clinically utilized chemotherapeutic agents (S- and M-phase poisons), vinblastine, vinorelbine, cytosine arabinoside and gemcitabine. All the p53 activators induce reversible cell-cycle arrest in primary human fibroblasts and protect them from both S- and M-phase poisons. Furthermore, studies with p53-mutant cancer cell lines show that nutlin-3 and low dose actinomycin D do not affect the sensitivity of these cells to any of the chemotherapeutics tested. Thus, these two small molecules could be suitable choices for cyclotherapy regimes involving S- or M-phase poisons. In contrast, pre-incubation of p53-mutant cells with tenovin-6 or leptomycin B reduces the efficacy of vinca alkaloids, suggesting that these p53 activators could be effective as chemoprotectants if combined with S- but not M-phase poisons. Discrepancies were observed between the levels of protection detected immediately after treatment and following recovery in fresh medium. This highlights the need to assess both short- and long-term effects when evaluating compounds as potential chemoprotectants for cancer therapy.
authors.affiliation: Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingeborg M M
authors.initials: IM
authors.lastname: van Leeuwen
authors.forename: Bhavya
authors.initials: B
authors.lastname: Rao
authors.forename: Marijke C C
authors.initials: MC
authors.lastname: Sachweh
authors.forename: Sonia
authors.initials: S
authors.lastname: Laín
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002452:Cell Count; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D003561:Cytarabine / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D005231:Fatty Acids, Unsaturated; D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014748:Vinca Alkaloids; C574854:tenovin-6; D003561:Cytarabine; D003609:Dactinomycin; C482205:nutlin 3; D014747:Vinblastine; D000077235:Vinorelbine; C038753:leptomycin B