Hwang, Jae Youn and Lubow, Jay and Chu, David and Ma, Jun and Agadjanian, Hasmik and Sims, Jessica and Gray, Harry B. and Gross, Zeev and Farkas, Daniel L. and Medina-Kauwe, Lali K. (2011) A Mechanistic Study of Tumor-Targeted Corrole Toxicity. Molecular Pharmaceutics, 8 (6). pp. 2233-2243. ISSN 1543-8384 http://resolver.caltech.edu/CaltechAUTHORS:20120203-102207173
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HerGa is a self-assembled tumor-targeted particle that bears both tumor detection and elimination activities in a single, two-component complex (Agadjanian et al. Proc. Natl. Acad. Sci. U.S.A.2009, 106, 6105–6110). Given its multifunctionality, HerGa (composed of the fluorescent cytotoxic corrole macrocycle, S2Ga, noncovalently bound to the tumor-targeted cell penetration protein, HerPBK10) has the potential for high clinical impact, but its mechanism of cell killing remains to be elucidated, and hence is the focus of the present study. Here we show that HerGa requires HerPBK10-mediated cell entry to induce toxicity. HerGa (but not HerPBK10 or S2Ga alone) induced mitochondrial membrane potential disruption and superoxide elevation, which were both prevented by endosomolytic-deficient mutants, indicating that cytosolic exposure is necessary for corrole-mediated cell death. A novel property discovered here is that corrole fluorescence lifetime acts as a pH indicator, broadcasting the intracellular microenvironmental pH during uptake in live cells. This feature in combination with two-photon imaging shows that HerGa undergoes early endosome escape during uptake, avoiding compartments of pH < 6.5. Cytoskeletal disruption accompanied HerGa-mediated mitochondrial changes whereas oxygen scavenging reduced both events. Paclitaxel treatment indicated that HerGa uptake requires dynamic microtubules. Unexpectedly, low pH is insufficient to induce release of the corrole from HerPBK10. Altogether, these studies identify a mechanistic pathway in which early endosomal escape enables HerGa-induced superoxide generation leading to cytoskeletal and mitochondrial damage, thus triggering downstream cell death.
|Additional Information:||© 2011 American Chemical Society. Published In Issue December 05, 2011; Article ASAP October 25, 2011; Just Accepted Manuscript October 10, 2011; Received: February 25, 2011; Accepted: October 09, 2011; Revised: July 19, 2011. L.K.M.-K. thanks J.C., D.R., and M.M.-K. for continued support. This work was supported by grants to L.K.M.-K. from the NIH (R21 CA116014, R01 CA102126, R01 CA129822, and R01 CA140995), the DoD (BC050662), the Susan G. Komen Breast Cancer foundation (BCTR0201194), and the Donna and Jesse Garber Award. Work at Caltech was supported by NIH DK019038 and the Arnold and Mabel Beckman Foundation. Work at the Technion was supported by The Herbert Irving Cancer and Atherosclerosis Research Fund.|
|Subject Keywords:||superoxide; mitochondria; cytoskeleton; tumor; targeting; gallium; corrole; heregulin; mechanism; HerGa|
|Official Citation:||A Mechanistic Study of Tumor-Targeted Corrole Toxicity Jae Youn Hwang, Jay Lubow, David Chu, Jun Ma, Hasmik Agadjanian, Jessica Sims, Harry B. Gray, Zeev Gross, Daniel L. Farkas, and Lali K. Medina-Kauwe Molecular Pharmaceutics 2011 8 (6), 2233-2243|
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|Deposited By:||Jason Perez|
|Deposited On:||03 Feb 2012 19:46|
|Last Modified:||26 Dec 2012 14:47|
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