Hyperploidy induced by drugs that inhibit formation of microtubule promotes chromosome instability.

Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Genes to Cells (Impact Factor: 2.73). 03/2002; 7(2):151-62. DOI: 10.1046/j.1356-9597.2001.00509.x
Source: PubMed

ABSTRACT Antimicrotubule drugs (AMDs), such as taxol and vincristine, are the most important addition to the chemotherapeutic armamentarium against human cancers. It has been shown that prolonged AMD treatment induces hyperploidy in G1-checkpoint-defective cancer cells and that these hyperploid cells subsequently undergo apoptosis. However, a fraction of these hyperploid cells are able to survive the prolonged mitotic stress and resume cell-cycle progression.
We established hyperploid clones that escaped from cell death after AMD treatment from two glioma cell lines, U251MG and U87MG. Subtractive comparative genomic hybridization (CGH) analysis revealed that clones derived from U87MG mainly had chromosome number changes, but that those from U251MG showed both numerical and structural chromosomal changes. Furthermore, numerous aberrations identified in U251MG clones were remarkably chromosome-specific, which may have been due to clonal selection for cells that have an advantage in growth and/or survival. All clones derived from both cell lines had abnormalities in chromosome segregation, and karyotypes of clones were more heterogeneous than those of parental cells, suggesting that cells having a higher chromosome number are subject to asymmetric chromosome segregation, resulting in a heterogeneous karyotype. All clones derived from U87MG and U251MG increased both centric and acentromeric micronuclei, suggesting the presence of chromosome structural abnormality.
AMD treatment induces hyperploid formation and chromosome instability in checkpoint-deficient cancer cells.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Structurally altered or marker chromosomes are the cytogenetic hallmarks of cancer cells, but their origins are still debated. Here we propose that aneuploidy, which is ubiquitous in cancer and inevitably unbalances thousands of synergistic genes, destabilizes the structure of chromosomes by catalyzing DNA breaks. Aneuploidy catalyzes such breaks by unbalancing teams of enzymes, which synthesize and maintain DNA and nucleotide pools, and even unbalancing histones via the corresponding genes. DNA breaks then initiate deletions, amplifications, and intra- and interchromosomal rearrangements. Our hypothesis predicts that the rate at which chromosomes are altered is proportional to the degree of aneuploidy: the more abnormal the number and balance of chromosomes, the higher the rate of structural alterations. To test this prediction, we have determined the rates at which clonal cultures of diploid and aneuploid Chinese hamster cells generate new, and thus nonclonal, structurally altered chromosomes per mitosis. Based on about 20 metaphases, the number of new, structurally altered chromosomes was 0 per diploid, 0-0.23 per near-diploid, 0.2-1.4 per hypotriploid, 3.25-4.8 per hypertriploid, and 0.4 per near-tetraploid cell. Thus, instability of chromosome structure increases exponentially with the deviation of ploidy from the normal diploid and tetraploid balances. The particular chromosomes engaged in aneuploidy also affected the rates of chromosome alteration, particularly at low aneuploidy indices. We conclude that aneuploidy is sufficient to cause structural instability of chromosomes. Further, we suggest that certain structurally altered chromosomes encode cancer-specific phenotypes that cannot be generated by unbalancing intact chromosomes. We also extend the evidence for aneuploidy causing numerical instability of chromosomes autocatalytically, and adduce evidence that aneuploidy can cause the many gene mutations of cancer cells that have been attributed to various mutator genes.
    Cancer Genetics and Cytogenetics 06/2003; 143(1):59-72. · 1.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: This study provides the data regarding monitoring of population using CB-micronuclei assay in the period 1995-2001 in Serbia. The target groups consisted of 45 pregnant women of mean age 34.3(6.56) years, unaware of being exposed to chemicals drugs or other substances and undergoing cordocentesis. The incidence of micronuclei (MN) in peripheral blood lymphocytes and in fetal cord blood lymphocytes was analyzed. METHODS: The study was carried out on cultures of PHA-stimulated blood lymphocytes. Three drops of blood samples ware added into 5ml RPMI-1640 (Gibco) medium supplemented with 15% of calf serum and PHA (Gibco, 2.5µg/ml). For micronuclei preparation the cytokinesis block method was used (Fenech et al., 1993). RESULTS: The results of the study showed that in the year 1995, the incidence of micronuclei in pregnant women was 9.61(3.26) per 1000 binucleated (BN) cells, and 3.74(1.60) in cord blood samples per 1000 BN cells, respectively. In 2000 the incidence of micronuclei in study group was 28.26(7.87) per 1000 BN cells, and in cord blood samples 22.22(5.63) per 1000 BN cells. One year later (2001) the incidence of micronuclei in pregnant woman slightly decreased and reached the value of 26.98(4.50), while in cord blood it slightly increased up to 26.58(6.85) per 1000 BN cells. CONCLUSION: The monitoring data obtained in this study have shown significantly increase of micronuclei (2- to 3-fold) in study groups in 2000 and 2001.
    Archive of Oncology. 01/2004;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pseudolaric acid B (PAB) is the primary biologically active compound isolated from the root bark of P. kaempferi Gordon. Previous studies have demonstrated that PAB arrests cells in G2/M phase in several cancer cell lines without significantly perturbing the G2/M transition-associated proteins. CylinB1, a marker for mitotic phase arrest, was up-regulated in cells treated with PAB. Therefore, we investigated whether PAB affects cell cycle progression at the mitotic phase. The mitotic index increased during a 24h treatment with PAB, suggesting that PAB arrested cell cycle progression at mitosis. In addition, after a prolonged mitotic arrest, the cells underwent mitotic catastrophe. After an extended treatment with PAB (longer than 24h), the protein levels of cylinB1 and cdc2 significantly decreased in both nuclear and cytosolic extracts. According to these results, we concluded that mitotic slippage could be due to the inactivation of the cylinB1-cdc2 complex resulting from prolonged treatment with PAB. The cells undergoing mitotic catastrophe died via apoptosis.
    European journal of pharmacology 03/2012; 683(1-3):16-26. · 2.59 Impact Factor

Full-text (2 Sources)

Available from
Oct 10, 2014