title: Effects of Anticancer Drugs on Chromosome Instability and New Clinical Implications for Tumor-Suppressing Therapies.
abstract: Whole chromosomal instability (CIN), manifested as unequal chromosome distribution during cell division, is a distinguishing feature of most cancer types. CIN is generally considered to drive tumorigenesis, but a threshold level exists whereby further increases in CIN frequency in fact hinder tumor growth. While this attribute is appealing for therapeutic exploitation, drugs that increase CIN beyond this therapeutic threshold are currently limited. In our previous work, we developed a quantitative assay for measuring CIN based on the use of a nonessential human artificial chromosome (HAC) carrying a constitutively expressed EGFP transgene. Here, we used this assay to rank 62 different anticancer drugs with respect to their effects on chromosome transmission fidelity. Drugs with various mechanisms of action, such as antimicrotubule activity, histone deacetylase inhibition, mitotic checkpoint inhibition, and targeting of DNA replication and damage responses, were included in the analysis. Ranking of the drugs based on their ability to induce HAC loss revealed that paclitaxel, gemcitabine, dactylolide, LMP400, talazoparib, olaparib, peloruside A, GW843682, VX-680, and cisplatin were the top 10 drugs demonstrating HAC loss at a high frequency. Therefore, identification of currently used compounds that greatly increase chromosome mis-segregation rates should expedite the development of new therapeutic strategies to target and leverage the CIN phenotype in cancer cells.
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Hee-Sheung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Nicholas C O
authors.initials: NC
authors.lastname: Lee
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Natalay
authors.initials: N
authors.lastname: Kouprina
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
authors.forename: Alex
authors.initials: A
authors.lastname: Kagansky
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Susan
authors.initials: S
authors.lastname: Bates
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland. larionov@mail.nih.gov sackettd@mail.nih.gov.
authors.forename: Dan
authors.initials: D
authors.lastname: Sackett
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, Maryland. larionov@mail.nih.gov sackettd@mail.nih.gov.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Larionov
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D019076:Transgenes
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