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Cellular uptake and anticancer activity of carboxylated gallium corroles

Pribisko, Melanie and Palmer, Joshua and Grubbs, Robert H. and Gray, Harry B. and Termini, John and Lim, Punnajit (2016) Cellular uptake and anticancer activity of carboxylated gallium corroles. Proceedings of the National Academy of Sciences of the United States of America, 113 (16). E2258-E2266. ISSN 0027-8424. PMCID PMC4843456. doi:10.1073/pnas.1517402113.

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We report derivatives of gallium(III) tris(pentafluorophenyl)corrole, 1 [Ga(tpfc)], with either sulfonic (2) or carboxylic acids (3, 4) as macrocyclic ring substituents: the aminocaproate derivative, 3 [Ga(ACtpfc)], demonstrated high cytotoxic activity against all NCI60 cell lines derived from nine tumor types and confirmed very high toxicity against melanoma cells, specifically the LOX IMVI and SK-MEL-28 cell lines. The toxicities of 1, 2, 3, and 4 [Ga(3-ctpfc)] toward prostate (DU-145), melanoma (SK-MEL-28), breast (MDA-MB-231), and ovarian (OVCAR-3) cancer cells revealed a dependence on the ring substituent: IC_(50) values ranged from 4.8 to >200 µM; and they correlated with the rates of uptake, extent of intracellular accumulation, and lipophilicity. Carboxylated corroles 3 and 4, which exhibited about 10-fold lower IC_(50) values (<20 µM) relative to previous analogs against all four cancer cell lines, displayed high efficacy (E_(max) = 0). Confocal fluorescence imaging revealed facile uptake of functionalized gallium corroles by all human cancer cells that followed the order: 4 >> 3 > 2 >> 1 (intracellular accumulation of gallium corroles was fastest in melanoma cells). We conclude that carboxylated gallium corroles are promising chemotherapeutics with the advantage that they also can be used for tumor imaging.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Grubbs, Robert H.0000-0002-0057-7817
Gray, Harry B.0000-0002-7937-7876
Termini, John0000-0002-4043-7552
Lim, Punnajit0000-0002-0159-1549
Additional Information:© 2016 National Academy of Sciences. Contributed by Harry B. Gray, March 1, 2016 (sent for review September 1, 2015; reviewed by David Dolphin and Daniel T. Gryko). Published online before print April 4, 2016. The experimental assistance of Dr. Shane Mangold and software assistance of Dr. Ching Ouyang are gratefully acknowledged. We thank Dr. Brian Armstrong of the Light Microscopy Digital Imaging Core Facility and Dr. Gerald Wuenschell of the Translational Biomarker Discovery Core Facility of the City of Hope Comprehensive Cancer Center for their technical assistance, and the NCI Developmental Therapeutics Program for the 60 cell line screen. This work was supported by a Caltech/COH grant (to J.T. and H.B.G.) and by NIH Grant DK01038 (to H.B.G.). uthor contributions: M.P., J.P., R.H.G., H.B.G., J.T., and P.L. designed research; M.P. and P.L. performed research; M.P. and P.L. contributed new reagents/analytic tools; M.P., J.T., and P.L. analyzed data; and M.P., J.P., R.H.G., H.B.G., J.T., and P.L. wrote the paper. Reviewers: D.D., University of British Columbia; and D.T.G., Polish Academy of Sciences. The authors declare no conflict of interest.
Funding AgencyGrant Number
Caltech-City of Hope Biomedical InitiativeUNSPECIFIED
Subject Keywords:carboxylated metallocorroles, gallium(III), corroles, macrocycles, anticancer agents
Issue or Number:16
PubMed Central ID:PMC4843456
Record Number:CaltechAUTHORS:20160405-091631208
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Official Citation:Melanie Pribisko, Joshua Palmer, Robert H. Grubbs, Harry B. Gray, John Termini, and Punnajit Lim Cellular uptake and anticancer activity of carboxylated gallium corroles PNAS 2016 113 (16) E2258-E2266; published ahead of print April 4, 2016, doi:10.1073/pnas.1517402113
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:65919
Deposited On:05 Apr 2016 16:40
Last Modified:05 May 2022 16:59

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