title: Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy.
abstract: p53-Based cyclotherapy is proving to be a promising approach to palliate undesired effects of chemotherapy in patients with tumours carrying p53 mutations. For example, pre-treatment of cell cultures with Nutlin-3, a highly-selective inhibitor of the p53-mdm2 interaction, has been successfully used as a cytostatic agent to protect normal cells, but not p53-defective cells, from subsequent treatment with mitotic poisons or S-phase specific drugs. Here we sought to evaluate whether low doses of Actinomycin D (LDActD), a clinically-approved drug and potent p53 activator, could substitute Nutlin-3 in p53-based cyclotherapy. We found that pre-treatment with LDActD before adding the aurora kinase inhibitor VX-680 protects normal fibroblasts from polyploidy and nuclear morphology abnormalities induced by VX-680. However, and although to a lower extent than normal fibroblasts, tumour cell lines bearing p53 mutations were also protected by LDActD (but not Nutlin-3) from VX-680-induced polyploidy. We also report that a difference between the response of p53 wild-type cells and p53-defective cells to the LDActD/VX-680 sequential combination is that only the former fail to enter S-phase and therefore accumulate in G1/G0. We propose that drugs that incorporate into DNA during S-phase may perform better as second drugs than mitotic poisons in cyclotherapy approaches using LDActD as a cytostatic agent.
authors.affiliation: Centre for Oncology & Molecular Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, Tayside, UK.
authors.forename: Bhavya
authors.initials: B
authors.lastname: Rao
authors.affiliation: Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Ingeborg M M
authors.initials: IMM
authors.lastname: van Leeuwen
authors.affiliation: Centre for Oncology & Molecular Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, Tayside, UK.
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.affiliation: Centre for Oncology & Molecular Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, Tayside, UK.
authors.forename: Johanna
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Centre for Oncology & Molecular Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, Tayside, UK.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: p53 Laboratory (A*STAR), 8A Biomedical Grove, #06-06, Immunos S138648, Singapore.
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.affiliation: Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
authors.forename: Sonia
authors.initials: S
authors.lastname: Lain
mesh_terms: D024422:Aneugens / Q000008:administration & dosage / Q000494:pharmacology; D000782:Aneuploidy; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D003609:Dactinomycin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D055786:Gene Knockout Techniques; D016158:Genes, p53 / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D024422:Aneugens; D064127:Aurora Kinases; D003609:Dactinomycin; D007093:Imidazoles; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C482205:nutlin 3