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Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers.

ABSTRACT: A limited decrease in mitochondrial membrane potential can be beneficial for cells, especially under some pathological conditions, suggesting that mild uncouplers (protonophores) causing such an effect are promising candidates for therapeutic uses. The great majority of protonophores are weak acids capable of permeating across membranes in their neutral and anionic forms. In the present study, protonophorous activity of a series of derivatives of cationic rhodamine 19, including dodecylrhodamine (C(12)R1) and its conjugate with plastoquinone (SkQR1), was revealed using a variety of assays. Derivatives of rhodamine B, lacking dissociable protons, showed no protonophorous properties. In planar bilayer lipid membranes, separating two compartments differing in pH, diffusion potential of H(+) ions was generated in the presence of C(12)R1 and SkQR1. These compounds induced pH equilibration in liposomes loaded with the pH probe pyranine. C(12)R1 and SkQR1 partially stimulated respiration of rat liver mitochondria in State 4 and decreased their membrane potential. Also, C(12)R1 partially stimulated respiration of yeast cells but, unlike the anionic protonophore FCCP, did not suppress their growth. Loss of function of mitochondrial DNA in yeast (grande-petite transformation) is known to cause a major decrease in the mitochondrial membrane potential. We found that petite yeast cells are relatively more sensitive to the anionic uncouplers than to C(12)R1 compared with grande cells. Together, our data suggest that rhodamine 19-based cationic protonophores are self-limiting; their uncoupling activity is maximal at high membrane potential, but the activity decreases membrane potentials, which causes partial efflux of the uncouplers from mitochondria and, hence, prevents further membrane potential decrease.

SUBMITTER: Antonenko YN

PROVIDER: S-EPMC3093858 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other

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Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers.

Antonenko Yuri N YN Avetisyan Armine V AV Cherepanov Dmitry A DA Knorre Dmitry A DA Korshunova Galina A GA Markova Olga V OV Ojovan Silvia M SM Perevoshchikova Irina V IV Pustovidko Antonina V AV Rokitskaya Tatyana I TI Severina Inna I II Simonyan Ruben A RA Smirnova Ekaterina A EA Sobko Alexander A AA Sumbatyan Natalia V NV Severin Fedor F FF Skulachev Vladimir P VP

The Journal of biological chemistry 20110330 20

A limited decrease in mitochondrial membrane potential can be beneficial for cells, especially under some pathological conditions, suggesting that mild uncouplers (protonophores) causing such an effect are promising candidates for therapeutic uses. The great majority of protonophores are weak acids capable of permeating across membranes in their neutral and anionic forms. In the present study, protonophorous activity of a series of derivatives of cationic rhodamine 19, including dodecylrhodamine ...[more]

PMID: 21454507

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Project description:In this study, we evaluated Cu(L1) in two xenografted tumor-bearing (U87MG and MDA-MB-435) animal models to prove the concept that Cu(II)-labeled rhodamine derivatives, Cu(L) (L = L1 - L4) are useful as selective fluorescent probes for tumor imaging. We found that both multidrug resistance (MDR) negative U87MG gliomas and MDR-positive MDA-MB-435 breast tumors could be visualized. Because of tissue attenuation, accurate quantification of tumor uptake was difficult by optical methods. Therefore, (64)Cu(L) (L = L1 - L4) were evaluated to compare their biodistribution properties. It was found that all four (64)Cu radiotracers had a high glioma uptake ((64)Cu(L1): 5.71± 1.43 %ID/g; (64)Cu(L2): 5.98 ± 2.75 %ID/g; (64)Cu(L3): 4.28 ± 1.45 %ID/g; and (64)Cu(L4): 6.25 ± 3.42 %ID/g) with (64)Cu(L1) showing the highest tumor/background ratios. In athymic nude mice bearing MDA-MB-435 breast cancer xenografts, (64)Cu(L4) showed almost identical normal organ uptake to that in the glioma-bearing animals, but its breast tumor uptake (1.26 ± 0.10% ID/g) was significantly lower (p < 0.001) than that in the glioma (6.25 ± 3.42% ID/g) because of MDR Pgps (P-glycoproteins) and MRPs (multidrug resistance-associated proteins) overexpressed in the xenografted MDA-MB-435 breast tumors. Results from cellular staining assays showed that both Cu(L2) and Cu(L4) were able to localize in mitochondria of U87MG cells, and their tumor selectivity was caused by the elevated negative mitochondrial potential in U87MG glioma cells as compared to that in human fibroblast cells. On the basis of these results, it was concluded that Cu(L) (L = L1 - L4) are useful as selective fluorescent probes for cellular staining assays and optical tumor imaging while (64)Cu(L) (L = L1 - L4) have the potential as PET radiotracers for tumor imaging. This study represents a good example of dual modality imaging (PET and optical) using two agents, (64)Cu(L) and Cu(L), with identical chemical composition. Future research will focus on developing new fluorescent probes with longer wavelength and reduced liver uptake.

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Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers.

Publications

Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers.

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