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Nucleic Acids Research 2006 34(6):1721-1734; doi:10.1093/nar/gkl063
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Published online 29 March 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

Novel GC-rich DNA-binding compound produced by a genetically engineered mutant of the mithramycin producer Streptomyces argillaceus exhibits improved transcriptional repressor activity: implications for cancer therapy

Veronica Albertini, Aklank Jain, Sara Vignati, Sara Napoli, Andrea Rinaldi, Ivo Kwee, Mohammad Nur-e-Alam1, Julia Bergant1, Francesco Bertoni, Giuseppina M. Carbone, Jürgen Rohr1,* and Carlo V. Catapano*

Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland Bellinzona, Switzerland 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky 725 Rose Street, Lexington, KY 40536-0082, USA

*To whom correspondence should be addressed. Tel: +41 91 820 0365; Fax: +41 91 820 0397; Email: carlo.catapano{at}irb.unisi.ch

Received January 24, 2006. Revised February 13, 2006. Accepted February 28, 2006.

The aureolic acid antibiotic mithramycin (MTM) binds selectively to GC-rich DNA sequences and blocks preferentially binding of proteins, like Sp1 transcription factors, to GC-rich elements in gene promoters. Genetic approaches can be applied to alter the MTM biosynthetic pathway in the producing microorganism and obtain new products with improved pharmacological properties. Here, we report on a new analog, MTM SDK, obtained by targeted gene inactivation of the ketoreductase MtmW catalyzing the last step in MTM biosynthesis. SDK exhibited greater activity as transcriptional inhibitor compared to MTM. SDK was a potent inhibitor of Sp1-dependent reporter activity and interfered minimally with reporters of other transcription factors, indicating that it retained a high degree of selectivity toward GC-rich DNA-binding transcription factors. RT–PCR and microarray analysis showed that SDK repressed transcription of multiple genes implicated in critical aspects of cancer development and progression, including cell cycle, apoptosis, migration, invasion and angiogenesis, consistent with the pleiotropic role of Sp1 family transcription factors. SDK inhibited proliferation and was a potent inducer of apoptosis in ovarian cancer cells while it had minimal effects on viability of normal cells. The new MTM derivative SDK could be an effective agent for treatment of cancer and other diseases with abnormal expression or activity of GC-rich DNA-binding transcription factors.

Correspondence may also be addressed to Jürgen Rohr. Tel: +1 859 323 5031; Fax: +1 859 257 7564; Email: jrohr2{at}email.uky.edu


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