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


RESULTS
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.


CONCLUSIONS
AMD treatment induces hyperploid formation and chromosome instability in checkpoint-deficient cancer cells.
Nitta
Masayuki
M
Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Tsuiki
Hiromasa
H
Arima
Yoshimi
Y
Harada
Kei
K
Nishizaki
Takahumi
T
Sasaki
Kousuke
K
Mimori
Tatsuyuki
T
Ushio
Yukitaka
Y
Saya
Hideyuki
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002875:Chromosomes / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology*; D011123:Polyploidy; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014750:Vincristine; D015739:Nocodazole