Lim, Punnajit and Mahammed, Atif and Okun, Zoya and Saltsman, Irena and Gross, Zeev and Gray, Harry B. and Termini, John (2012) Differential Cytostatic and Cytotoxic Action of Metallocorroles against Human Cancer Cells: Potential Platforms for Anticancer Drug Development. Chemical Research in Toxicology, 25 (2). pp. 400-409. ISSN 0893-228X http://resolver.caltech.edu/CaltechAUTHORS:20120323-091012038
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A gallium(III)-substituted amphiphilic corrole noncovalently associated with a targeting protein was previously found by us to confer promising cytotoxic and antitumor activities against a breast cancer cell line and a mouse xenograft breast cancer model. To further explore potential anticancer applications, the cytostatic and cytotoxic properties of six nontargeted metallocorroles were evaluated against seven human cancer cell lines. Results indicated that toxicity toward human cancer cells depended on the metal ion as well as corrole functional group substitution. Ga(III)-substituted metallocorrole 1-Ga inhibited proliferation of breast (MDA-MB-231), melanoma (SK-MEL-28), and ovarian (OVCAR-3) cancer cells primarily by arrest of DNA replication, whereas 2-Mn displayed both cytostatic and cytotoxic properties. Confocal microscopy revealed extensive uptake of 1-Ga into the cytoplasm of melanoma and ovarian cancer cells, while prostate cancer cells (DU-145) displayed extensive nuclear localization. The localization of 1-Ga to the nucleus in DU-145 cells was exploited to achieve a 3-fold enhancement in the IC_(50) of doxorubicin upon coadministration. Time–course studies showed that over 90% of melanoma cells incubated with 30 μM 1-Ga internalized metallocorrole after 15 min. Cellular uptake of 1-Ga and 1-Al was fastest and most efficient in melanoma, followed by prostate and ovarian cancer cells. Cell cycle analyses revealed that bis-sulfonated corroles containing Al(III), Ga(III), and Mn(III) induced late M phase arrest in several different cancer cell lines, a feature that could be developed for potential therapeutic benefit.
|Additional Information:||© 2011 American Chemical Society. Received: October 18, 2011. Publication Date (Web): December 20, 2011. The technical assistance of Dr. Richard Yip and Charlie Hsin of the High Throughput Screening and Dr. Brian Armstrong of the Light Microscopy Digital Imaging Core Facilities of the City of Hope Comprehensive Cancer Center is gratefully acknowledged. This work was supported by Caltech-City of Hope Biomedical Research Initiative and the U.S. Army RDECOM Acquisition Center, Natick Contracting Division, Natick, MA, under Contract no. W911QY-10-C-0176|
|Official Citation:||Differential Cytostatic and Cytotoxic Action of Metallocorroles against Human Cancer Cells: Potential Platforms for Anticancer Drug Development Punnajit Lim, Atif Mahammed, Zoya Okun, Irena Saltsman, Zeev Gross, Harry B. Gray, and John Termini Chemical Research in Toxicology 2012 25 (2), 400-409|
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|Deposited By:||Ruth Sustaita|
|Deposited On:||23 Mar 2012 16:59|
|Last Modified:||26 Dec 2012 14:58|
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