Differential cytostatic and cytotoxic action of Metallocorroles against human cancer cells: potential platforms for anticancer drug development.

Abstract

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.

• Authors: Punnajit Lim, Atif Mahammed, Zoya Okun, Irena Saltsman, Zeev Gross, Harry B Gray, John Termini
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 25 Issue 2 Pg. 400-9 (Feb 20 2012) ISSN: 1520-5010 [Electronic] United States
• PMID: 22185566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytostatic Agents
• Cytotoxins
• Metals
• Organometallic Compounds
• Porphyrins
• corrole

Topics

• Cell Line, Tumor
• Cell Survival (drug effects)
• Cytostatic Agents (chemistry, toxicity)
• Cytotoxins (chemistry, toxicity)
• Drug Design
• Humans
• Metals (chemistry)
• Neoplasms (drug therapy)
• Organometallic Compounds (toxicity)
• Porphyrins (chemistry)