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Asano, T. et al.

Asano, Nakamura, Fujii, Horichi, Ohmori, Hasegawa, Isoe, Adachi, Otake, Fukunaga,

Altered expression of topoisomerase IIalpha contributes to cross-resistant to etoposide K562/ MX2 cell line by aberrant methylation.

KRN 8602 ( MX2) is a novel morpholino anthracycline derivative having the chemical structure 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. To investigate the mechanisms of resistance to MX2, we established an MX2-resistant phenotype (K562/ MX2) of the human myelogeneous leukaemia cell line (K562/P), by continuously exposing a suspension culture to increasing concentrations of MX2. K562/ MX2 cells were more resistant to MX2 than the parent cells, and also showed cross-resistance to etoposide and doxorubicin. Topoisomerase (Topo) IIalpha protein levels in K562/ MX2 cells were lower of those in K562/P cells on immunoblot analysis and decreased expression of Topo IIalpha mRNA was seen in K562/ MX2 cells. Topoisomerase II catalytic activity was also reduced in the nuclear extracts from K562/ MX2 cells when compared with K562/P cells. Aberrant methylated CpG of Topo IIalpha gene was observed in K562/ MX2 cells when compared with the parent line on methylation-specific restriction enzyme analysis. To overcome the drug resistance to MX2 and etoposide, we investigated treatment with 5-Aza-2'-deoxycytidine (5AZ), which is a demethylating agent, in K562/ MX2 cells. 5-Aza-2'-deoxycytidine treatment increased Topo IIalpha mRNA expression in K562/ MX2 cells, but not in K562/P cells, and increased the cytotoxicity of MX2 and etoposide. Methylated CpG was decreased in K562/ MX2 cells after 5AZ treatment. We concluded that the mechanism of drug resistance to MX2 and etoposide in K562/ MX2 cells might be the combination of decreased expression of Topo IIalpha gene and increased methylation, and that 5AZ could prove to be a novel treatment for etoposide-resistant cell lines, such as K562/ MX2.[1]

References

Altered expression of topoisomerase IIalpha contributes to cross-resistant to etoposide K562/MX2 cell line by aberrant methylation. Asano, T., Nakamura, K., Fujii, H., Horichi, N., Ohmori, T., Hasegawa, K., Isoe, T., Adachi, M., Otake, N., Fukunaga, Y. Br. J. Cancer (2005) [Pubmed]

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