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    Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression

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    Date
    2007-01-19
    Author
    Wang, Zhong
    Lecane, Philip S.
    Thiemann, Patrica
    Fan, Qing
    Cortez, Cecilia
    Ma, Xuan
    Tonev, Danielle
    Miles, Dale
    Naumovski, Louie
    Miller, Richard A.
    Magda, Darren
    Cho, Dong-Gyu
    Sessler, Jonathan L.
    Pike, Brian L.
    Yeligar, Samantha M.
    Karaman, Mazen W.
    Hacia, Joseph G.
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    Abstract
    Background: Sapphyrin analogues and related porphyrin-like species have attracted attention as anticancer agents due to their selective localization in various cancers, including hematologic malignancies, relative to surrounding tissues. Sapphyrins are electron affinic compounds that generate high yields of singlet oxygen formation. Although initially explored in the context of photodynamic therapy, sapphyrins have intrinsic anticancer activity that is independent of their photosensitizing properties. However, the mechanisms for their anticancer activity have not been fully elucidated. -- Results: We have prepared a series of hydrophilic sapphyrins and evaluated their effect on proliferation, uptake, and cell death in adherent human lung (A549) and prostate (PC3) cancer cell lines and in an A549 xenograft tumor model. PCI-2050, the sapphyrin derivative with the highest in vitro growth inhibitory activity, significantly lowered 5-bromo-2'-deoxyuridine incorporation in S-phase A549 cells by 60% within eight hours and increased levels of reactive oxygen species within four hours. The growth inhibition pattern of PCI-2050 in the National Cancer Institute 60 cell line screen correlated most closely using the COMPARE algorithm with known transcriptional or translational inhibitors. Gene expression analyses conducted on A549 plateau phase cultures treated with PCI-2050 uncovered wide-spread decreases in mRNA levels, which especially affected short-lived transcripts. Intriguingly, PCI-2050 increased the levels of transcripts involved in RNA processing and trafficking, transcriptional regulation, and chromatin remodeling. We propose that these changes reflect the activation of cellular processes aimed at countering the observed wide-spread reductions in transcript levels. In our A549 xenograft model, the two lead compounds, PCI-2050 and PCI-2022, showed similar tumor distributions despite differences in plasma and kidney level profiles. This provides a possible explanation for the better tolerance of PCI-2022 relative to PCI-2050. -- Conclusion: Hydrophilic sapphyrins were found to display promise as novel agents that localize to tumors, generate oxidative stress, and inhibit gene expression.
    Department
    Chemistry
     
    Biochemistry
     
    Description
    Zhong Wang, Philip S. Lecane, Patricia Thiemann, Quing Fan, Cecilia Cortez, Xuan Ma, Danielle Tonev, Dale Miles, Louie Naumovski, and Richard A. Miller, Darren Magda are with the Pharmacyclics, Inc., Sunnyvale, California, USA -- Dong-Gyu Cho and Jonathan L. Sessler are with the Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas, USA -- Brian L. Pike, Samantha M. Yeligar, Mazen W. Laraman and Joseph G. Hacia are with the Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, USA
    Subject
    hydrophilic sapphyrins
    tumor-selective inhibitors
    gene expression
    anticancer agents
    URI
    http://hdl.handle.net/2152/27878
    Citation
    Wang, Zhong, Philip S. Lecane, Patricia Thiemann, Qing Fan, Cecilia Cortez, Xuan Ma, Danielle Tonev, et al. “Synthesis and Biologic Properties of Hydrophilic Sapphyrins, a New Class of Tumor-Selective Inhibitors of Gene Expression.” Molecular Cancer 6, no. 1 (January 19, 2007): 9. doi:10.1186/1476-4598-6-9.
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