Rhodamine-123 Selectively Reduces Clonal Growth of Carcinoma Cells in Vitro

Bernal, Samuel D.; Lampidis, Théodore J.; Summerhayes, Ian C.; Chen, Lan Bo

doi:10.1126/science.7146897

Cited by 163 publications

(100 citation statements)

References 13 publications

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“…Thus far, the members of Rhodamine family, including Rhodamine-6G, have been demonstrated to destroy various cell cultures when applied to the latter in high concentrations [9][10][11]. In a number of studies which happened to use lower concentrations of Rhodamine the latter was shown to selectively affect tumor cells by destruction of mitochondria via binding to their membranes [19][20][21][22][23][24]. It has been then suggested that Rhodamine might be selectively toxic towards at least some malignant cells in vitro [21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…In a number of studies which happened to use lower concentrations of Rhodamine the latter was shown to selectively affect tumor cells by destruction of mitochondria via binding to their membranes [19][20][21][22][23][24]. It has been then suggested that Rhodamine might be selectively toxic towards at least some malignant cells in vitro [21][22][23][24]. Among various explanations, it has been proposed that the mechanisms accounting for such selectivity might be the differences in the plasma membrane potential between normal and carcinoma cells [21].…”

Section: Discussionmentioning

confidence: 99%

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Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice

Kutushov

Gorelik²

2013

neo

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Rhodamine-6G is a fluorescent dye binding to mitochondria, thus reducing the intact mitochondria number and inhibiting mitochondrial metabolic activity. Resultantly, the respiratory chain functioning becomes blocked, the cell "suffocated" and eventually destroyed. Unlike normal cells, malignant cells demonstrate a priori reduced mitochondrial numbers and aberrant metabolism. Therefore, a turning point might exist, when Rhodamine-induced loss of active mitochondria would selectively destroy malignant, but spare normal cells. Various malignant vs. non-malignant cell lines were cultured with Rhodamine-6G at different concentrations. In addition, C57Bl mice were implanted with B16-F10 melanoma and treated with Rhodamine-6G at different dosage/time regimens. Viability and proliferation of cultured tumor cells were time and dose-dependently inhibited, up to 90%, by Rhodamine-6G, with profound histological signs of cell death. By contrast, inhibition of normal control cell proliferation hardly exceeded 15-17%. Melanoma-transplanted mice receiving Rhodamine-6G demonstrated prolonged survival, improved clinical parameters, inhibited tumor growth and metastases count, compared to their untreated counterparts. Twice-a-week 10 -6 M Rhodamine-6G regimen yielded the most prominent results. We conclude that malignant, but not normal, cells are selectively destroyed by low doses of Rhodamine-6G. In vivo, such treatment selectively suppresses tumor progression and dissemination, thus improving prognosis. We suggest that selective anti-tumor properties of Rhodamine-6G are based on unique physiologic differences in energy metabolism between malignant and normal cells. If found clinically relevant, low concentrations of Rhodamine-6G might be useful for replacing, or backing up, more aggressive nonselective chemotherapeutic compounds. Key words: warburg effect, tumor, cell culture, melanoma, rhodamine-6G, mitochondriaCancer cells are unique in their energy turnover. Unlike normal tissues that derive most of their energy by metabolizing the consumed sugar to carbon dioxide and water (the process taking place within mitochondria), tumors obtain as much as half of their ATP by metabolizing glucose directly to lactic acid. Normal tissues use the process of oxidative phosphorylation within mitochondria for 90% of ATP production, and only 10% is produced by glucose consumption. By contrast, in tumor cells this ratio is 50%:50% [1][2][3]. This unique pattern of tumor metabolism has been described in early thirties of the past century and has been recognized since then as Warburg effect [1][2][3]. Recent studies employing molecular biology and proteomic imaging technologies, explained the basics of Warburg effect [4,5].Rhodamine-6G is a fluorescent dye capable of penetrating a living cell [6]. Upon entering the cell, Rhodamine-6G binds to the inner membranes of mitochondria. Based on these observations, it has been proposed that Rhodamine dyes may be used for producing fluorescent images of mitochondria with low background noise and high re...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice

Kutushov

Gorelik²

2013

neo

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“…The mechanism of the selectivity of PM031379 for tumor versus normal cells mitochondria is under investigation. It has been known for some time that the constitutively higher Dw m of cancer cells is the driving force that selectively accumulates lipophilic cations, such as the smallmolecule F16 (30,31), in their mitochondria (35,36). Thus, it can be assumed that the protonation of the amino side chain of PM031379 reinforces the mitochondriophilic potential of lamellarin D.…”

Section: Discussionmentioning

confidence: 99%

Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D

et al. 2006

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Lamellarin D is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cell lines and is a potent inhibitor of topoisomerase I. However, lamellarin D maintains a marked cytotoxicity toward cell lines resistant to the reference topoisomerase I poison camptothecin. We therefore hypothesized that topoisomerase I is not the only cellular target for the drug. Using complementary cell-based assays, we provide evidence that lamellarin D acts on cancer cell mitochondria to induce apoptosis. Lamellarin D, unlike camptothecin, induces early disruption of the inner mitochondrial transmembrane potential (#y m ) in the P388 leukemia cell line. The functional alterations are largely prevented by cyclosporin A, an inhibitor of the mitochondrial permeability transition (MPT), but not by the inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone. #y m disruption is associated with mitochondrial swelling and cytochrome c leakage. Using a reliable real-time flow cytometric monitoring of #y m and swelling of mitochondria isolated from leukemia cells, we show that lamellarin D has a direct MPT-inducing effect. Furthermore, mitochondria are required in a cell-free system to mediate lamellarin D-induced nuclear apoptosis. The direct mitochondrial effect of lamellarin D accounts for the sensitivity of topoisomerase I-mutated P388CPT5 cells resistant to camptothecin. Interestingly, a tumor-active analogue of lamellarin D, designated PM031379, also exerts a direct proapoptotic action on mitochondria, with a more pronounced activity toward mitochondria of tumor cell lines compared with nontumor cell lines. Altogether, this work reinforces the pharmacologic interest of the lamellarins and defines lamellarin D as a lead in the search for treatments against chemoresistant cancer cells. (Cancer Res 2006; 66(6): 3177-87)

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“…It is well known that some slow response potentiometric indicators affect redox metabolism in mitochondria as well as cell proliferation (364). For example, rhodamine-123 is usually not retained within mitochondria of normal cells when extensively washed, but it is retained within mitochondria of carcinoma and heart muscle cells, resulting in inhibition of their proliferation (29,212,348,380). It has also been reported that fluo 3-loaded sea urchin eggs do not undergo normal development, whereas calcium green-loaded sea urchin eggs develop normally (378).…”

Section: B Cytotoxicitymentioning

confidence: 99%

Measurement of Intracellular Calcium

Takahashi

Camacho

Lechleiter

et al. 1999

Physiological Reviews

668

511

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To a certain extent, all cellular, physiological, and pathological phenomena that occur in cells are accompanied by ionic changes. The development of techniques allowing the measurement of such ion activities has contributed substantially to our understanding of normal and abnormal cellular function. Digital video microscopy, confocal laser scanning microscopy, and more recently multiphoton microscopy have allowed the precise spatial analysis of intracellular ion activity at the subcellular level in addition to measurement of its concentration. It is well known that Ca2+ regulates numerous physiological cellular phenomena as a second messenger as well as triggering pathological events such as cell injury and death. A number of methods have been developed to measure intracellular Ca2+. In this review, we summarize the advantages and pitfalls of a variety of Ca2+ indicators used in both optical and nonoptical techniques employed for measuring intracellular Ca2+ concentration.

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Rhodamine-123 Selectively Reduces Clonal Growth of Carcinoma Cells in Vitro

Cited by 163 publications

References 13 publications

Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice

Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice

Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D

Measurement of Intracellular Calcium

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