Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies

Anna M. Azarova, Yi Lisa Lyu, Chao P. Lin, Yuan Chin Tsai, J. Y N Lau, James C. Wang, Leroy F. Liu

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the β rather than the α isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2β+ than in skin-specific top2β-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2β-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2β-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2α-dependent. These results point to the importance of developing Top2α-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.

Original languageEnglish
Pages (from-to)11014-11019
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number26
DOIs
Publication statusPublished - Jun 26 2007
Externally publishedYes

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Keywords

  • Carcinogenesis
  • DNA rearrangements
  • Melanoma
  • Skin-specific topoisomerase IIβ-knockout
  • Tumor cell killing

ASJC Scopus subject areas

  • General
  • Genetics

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