Relevance of the chemical charge of rhodamine dyes to multiple drug resistance

Theodore Lampidis, Carlos Castello, Auro Del Giglio, Berton C. Pressman, Pierre Viallet, Kenneth W. Trevorrow, Gunther K. Valet, Haim Tapiero, Niramol Savaraj

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Abstract

Previously, we have shown that multiple drug resistant (MDR) Friend leukemia cells (FLC) are cross-resistant to the positively-charged dye, Rhodamine 123 (Rho 123), and that this resistance can be reversed by verapamil (VER). In the present study we used two zwitterionic rhodamine analogs, Rhodamine 116 and Rhodamine 110, and another positively-charged analog, Rhodamine 6G, to determine whether drug accumulation, resistance and modulation were affected by changes in the charge of these compounds. While there was no differential sensitivity between sensitive and resistant FLC to zwitterionic rhodamines, there was marked differential toxicity between these cell types for the positively charged analogs. The ic50 values were 1000- and 100-fold greater in resistant than in sensitive cells for Rho 123 and Rho6G respectively. Intracellular drug accumulation was significantly higher in sensitive as compared to resistant cells for both Rho 123 and Rho 6G, but little difference in drug uptake between these two cell types was observed for Rho 110 and Rho 116. It was also found that the intracellular to extracellular ratio of the positively-charged compounds was greater than unity in both sensitive and resistant cells whereas for the zwitterionic analogs this ratio was less than 1. Furthermore, this ratio of drug uptake was found to be significantly higher for Rho 6G than for Rho 123, which correlated with the high oil:water partition coefficient of Rho 6G (115.6). In MDR cells, verapamil increased Rho 123 and Rho 6G accumulation by 9.4- and 8.6-fold respectively. In addition, ic50 values in resistant cells were reduced >100-fold for Rho 6G and > 1000-fold for Rho 123 in the presence of 10 μg/ml of verapamil. In contrast, < 2-fold reduction of ic50 values for both of the zwitterionic analogs could be obtained under the same conditions. These results indicate that the chemical charge of rhodamines plays an important role in their differential accumulation, cytotoxicity and sensitivity to modulators such as verapamil, in sensitive and multi-drug resistant cells. The data also suggest that increased lipophilicity of the positively-charged rhodamines may increase their ability to accumulate in, and subsequently kill, MDR cells.

Original languageEnglish
Pages (from-to)4267-4271
Number of pages5
JournalBiochemical Pharmacology
Volume38
Issue number23
DOIs
StatePublished - Dec 1 1989

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Rhodamines
Multiple Drug Resistance
Rhodamine 123
Coloring Agents
Verapamil
Pharmaceutical Preparations
Inhibitory Concentration 50
Leukemia
Cytotoxicity
Modulators
Toxicity
Oils
Modulation
Drug Resistance
Water

ASJC Scopus subject areas

  • Pharmacology

Cite this

Relevance of the chemical charge of rhodamine dyes to multiple drug resistance. / Lampidis, Theodore; Castello, Carlos; Del Giglio, Auro; Pressman, Berton C.; Viallet, Pierre; Trevorrow, Kenneth W.; Valet, Gunther K.; Tapiero, Haim; Savaraj, Niramol.

In: Biochemical Pharmacology, Vol. 38, No. 23, 01.12.1989, p. 4267-4271.

Research output: Contribution to journalArticle

Lampidis, T, Castello, C, Del Giglio, A, Pressman, BC, Viallet, P, Trevorrow, KW, Valet, GK, Tapiero, H & Savaraj, N 1989, 'Relevance of the chemical charge of rhodamine dyes to multiple drug resistance', Biochemical Pharmacology, vol. 38, no. 23, pp. 4267-4271. https://doi.org/10.1016/0006-2952(89)90525-X
Lampidis T, Castello C, Del Giglio A, Pressman BC, Viallet P, Trevorrow KW et al. Relevance of the chemical charge of rhodamine dyes to multiple drug resistance. Biochemical Pharmacology. 1989 Dec 1;38(23):4267-4271. https://doi.org/10.1016/0006-2952(89)90525-X
Lampidis, Theodore ; Castello, Carlos ; Del Giglio, Auro ; Pressman, Berton C. ; Viallet, Pierre ; Trevorrow, Kenneth W. ; Valet, Gunther K. ; Tapiero, Haim ; Savaraj, Niramol. / Relevance of the chemical charge of rhodamine dyes to multiple drug resistance. In: Biochemical Pharmacology. 1989 ; Vol. 38, No. 23. pp. 4267-4271.
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abstract = "Previously, we have shown that multiple drug resistant (MDR) Friend leukemia cells (FLC) are cross-resistant to the positively-charged dye, Rhodamine 123 (Rho 123), and that this resistance can be reversed by verapamil (VER). In the present study we used two zwitterionic rhodamine analogs, Rhodamine 116 and Rhodamine 110, and another positively-charged analog, Rhodamine 6G, to determine whether drug accumulation, resistance and modulation were affected by changes in the charge of these compounds. While there was no differential sensitivity between sensitive and resistant FLC to zwitterionic rhodamines, there was marked differential toxicity between these cell types for the positively charged analogs. The ic50 values were 1000- and 100-fold greater in resistant than in sensitive cells for Rho 123 and Rho6G respectively. Intracellular drug accumulation was significantly higher in sensitive as compared to resistant cells for both Rho 123 and Rho 6G, but little difference in drug uptake between these two cell types was observed for Rho 110 and Rho 116. It was also found that the intracellular to extracellular ratio of the positively-charged compounds was greater than unity in both sensitive and resistant cells whereas for the zwitterionic analogs this ratio was less than 1. Furthermore, this ratio of drug uptake was found to be significantly higher for Rho 6G than for Rho 123, which correlated with the high oil:water partition coefficient of Rho 6G (115.6). In MDR cells, verapamil increased Rho 123 and Rho 6G accumulation by 9.4- and 8.6-fold respectively. In addition, ic50 values in resistant cells were reduced >100-fold for Rho 6G and > 1000-fold for Rho 123 in the presence of 10 μg/ml of verapamil. In contrast, < 2-fold reduction of ic50 values for both of the zwitterionic analogs could be obtained under the same conditions. These results indicate that the chemical charge of rhodamines plays an important role in their differential accumulation, cytotoxicity and sensitivity to modulators such as verapamil, in sensitive and multi-drug resistant cells. The data also suggest that increased lipophilicity of the positively-charged rhodamines may increase their ability to accumulate in, and subsequently kill, MDR cells.",
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N2 - Previously, we have shown that multiple drug resistant (MDR) Friend leukemia cells (FLC) are cross-resistant to the positively-charged dye, Rhodamine 123 (Rho 123), and that this resistance can be reversed by verapamil (VER). In the present study we used two zwitterionic rhodamine analogs, Rhodamine 116 and Rhodamine 110, and another positively-charged analog, Rhodamine 6G, to determine whether drug accumulation, resistance and modulation were affected by changes in the charge of these compounds. While there was no differential sensitivity between sensitive and resistant FLC to zwitterionic rhodamines, there was marked differential toxicity between these cell types for the positively charged analogs. The ic50 values were 1000- and 100-fold greater in resistant than in sensitive cells for Rho 123 and Rho6G respectively. Intracellular drug accumulation was significantly higher in sensitive as compared to resistant cells for both Rho 123 and Rho 6G, but little difference in drug uptake between these two cell types was observed for Rho 110 and Rho 116. It was also found that the intracellular to extracellular ratio of the positively-charged compounds was greater than unity in both sensitive and resistant cells whereas for the zwitterionic analogs this ratio was less than 1. Furthermore, this ratio of drug uptake was found to be significantly higher for Rho 6G than for Rho 123, which correlated with the high oil:water partition coefficient of Rho 6G (115.6). In MDR cells, verapamil increased Rho 123 and Rho 6G accumulation by 9.4- and 8.6-fold respectively. In addition, ic50 values in resistant cells were reduced >100-fold for Rho 6G and > 1000-fold for Rho 123 in the presence of 10 μg/ml of verapamil. In contrast, < 2-fold reduction of ic50 values for both of the zwitterionic analogs could be obtained under the same conditions. These results indicate that the chemical charge of rhodamines plays an important role in their differential accumulation, cytotoxicity and sensitivity to modulators such as verapamil, in sensitive and multi-drug resistant cells. The data also suggest that increased lipophilicity of the positively-charged rhodamines may increase their ability to accumulate in, and subsequently kill, MDR cells.

AB - Previously, we have shown that multiple drug resistant (MDR) Friend leukemia cells (FLC) are cross-resistant to the positively-charged dye, Rhodamine 123 (Rho 123), and that this resistance can be reversed by verapamil (VER). In the present study we used two zwitterionic rhodamine analogs, Rhodamine 116 and Rhodamine 110, and another positively-charged analog, Rhodamine 6G, to determine whether drug accumulation, resistance and modulation were affected by changes in the charge of these compounds. While there was no differential sensitivity between sensitive and resistant FLC to zwitterionic rhodamines, there was marked differential toxicity between these cell types for the positively charged analogs. The ic50 values were 1000- and 100-fold greater in resistant than in sensitive cells for Rho 123 and Rho6G respectively. Intracellular drug accumulation was significantly higher in sensitive as compared to resistant cells for both Rho 123 and Rho 6G, but little difference in drug uptake between these two cell types was observed for Rho 110 and Rho 116. It was also found that the intracellular to extracellular ratio of the positively-charged compounds was greater than unity in both sensitive and resistant cells whereas for the zwitterionic analogs this ratio was less than 1. Furthermore, this ratio of drug uptake was found to be significantly higher for Rho 6G than for Rho 123, which correlated with the high oil:water partition coefficient of Rho 6G (115.6). In MDR cells, verapamil increased Rho 123 and Rho 6G accumulation by 9.4- and 8.6-fold respectively. In addition, ic50 values in resistant cells were reduced >100-fold for Rho 6G and > 1000-fold for Rho 123 in the presence of 10 μg/ml of verapamil. In contrast, < 2-fold reduction of ic50 values for both of the zwitterionic analogs could be obtained under the same conditions. These results indicate that the chemical charge of rhodamines plays an important role in their differential accumulation, cytotoxicity and sensitivity to modulators such as verapamil, in sensitive and multi-drug resistant cells. The data also suggest that increased lipophilicity of the positively-charged rhodamines may increase their ability to accumulate in, and subsequently kill, MDR cells.

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