Modulation of cisplatin cytotoxicity by permeabilization of the plasma membrane by digitonin in vitro

Jekunen, Antti; Shalinsky, David R.; Hom, Doreen K.; Albright, Kathy D.; Heath, Dennis D.; Howell, Stephen B.

doi:10.1016/0006-2952(93)90019-s

Cited by 34 publications

(20 citation statements)

References 18 publications

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“…In the case of digitonin, our results show that, by permeating the membrane of a parasitic cell, the trypanocidal activity of almost any alkaloid is increased. A similar finding, in which the uptake of polar drugs was enhanced by the addition of digitonin, has been obtained from human cells (34). The strongest effect was measured when digitonin was added to vinblastine.…”

Section: Discussionsupporting

confidence: 80%

Combinations of Alkaloids Affecting Different Molecular Targets with the Saponin Digitonin Can Synergistically Enhance Trypanocidal Activity against Trypanosoma brucei brucei

Krstin

Peixoto

2015

Antimicrob Agents Chemother

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The flagellate Trypanosoma brucei causes sleeping sickness in humans and nagana in animals. Only a few drugs are registered to treat trypanosomiasis, but those drugs show severe side effects. Also, because some pathogen strains have become resistant, new strategies are urgently needed to combat this parasitic disease. An underexplored possibility is the application of combinations of several trypanocidal agents, which may potentiate their trypanocidal activity in a synergistic fashion. In this study, the potential synergism of mutual combinations of bioactive alkaloids and alkaloids with a membrane-active steroidal saponin, digitonin, was explored with regard to their effect on T. b. brucei. Alkaloids were selected that affect different molecular targets: berberine and chelerythrine (intercalation of DNA), piperine (induction of apoptosis), vinblastine (inhibition of microtubule assembly), emetine (intercalation of DNA, inhibition of protein biosynthesis), homoharringtonine (inhibition of protein biosynthesis), and digitonin (membrane permeabilization and uptake facilitation of polar compounds). Most combinations resulted in an enhanced trypanocidal effect. The addition of digitonin significantly stimulated the activity of almost all alkaloids against trypanosomes. The strongest effect was measured in a combination of digitonin with vinblastine. The highest dose reduction indexes (DRI) were measured in the two-drug combination of digitonin or piperine with vinblastine, where the dose of vinblastine could be reduced 9.07-fold or 7.05-fold, respectively. The synergistic effects of mutual combinations of alkaloids and of alkaloids with digitonin present a new avenue to treat trypanosomiasis but one which needs to be corroborated in future animal experiments.T rypanosoma brucei is a single-celled protozoan that, if left untreated, can cause the deadly sleeping sickness (human African trypanosomiasis [HAT]). Two trypanosome subspecies affect people: T. b. gambiense (found in western and central Africa) and T. b. rhodesiense (in eastern and southern Africa). The disease caused by T. b. gambiense is more abundant and accounts for more than 98% of all infections of patients. Infected persons go through two stages of the disease. The first or hemolymphatic phase causes fever, itching, and headache. In the second or neurological stage, the blood-brain barrier is crossed by the parasite and the central nervous system is affected. This is the stage at which the disturbance of the sleep cycle appears (hence the name of the disease). The vector of T. brucei is the tsetse fly (genus Glossina), which can transmit the parasite to a diversity of mammalian hosts, including humans (1, 2).Only four drugs are registered for treatment of the disease. Suramin and pentamidine are used for the first stage of the sleeping sicknesses caused by T. b. rhodesiense and T. b. gambiense, respectively. Melarsoprol is registered for treatment of the neurological stage. Eflornithine is a drug which is less toxic than melarsoprol but is effective on...

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Section: Discussionsupporting

confidence: 80%

Combinations of Alkaloids Affecting Different Molecular Targets with the Saponin Digitonin Can Synergistically Enhance Trypanocidal Activity against Trypanosoma brucei brucei

Krstin

Peixoto

2015

Antimicrob Agents Chemother

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“…If we consider the mechanism of action, most of them are due to the interaction of the aglycone with the sterol of the plasma membrane followed by aggregation of the carbohydrate moieties inducing the rearrangement of the phospholipid bilayer and the pore formation [5]. This provokes a leak of electrolytes and metabolites and increases the permeability of the plasma cell membrane.Quillaic-acid saponins of Quillaja saponaria and the steroid saponin digitonin of Digitalis purpurea were shown to promote the permeabilization of the plasma membrane in human leukemic H-L 60 cells [6] and in human ovarian carcinoma 2008 cells [7], respectively. In the course of our search for bioactive saponins from Caryophyllaceae, we describe here the effect of quillaicacid saponins, jenisseensosides A, B, C and D, (1 ± 4) (Chart 1) of two Silene species [8], [9] on the accumulation and cytotoxicity of cisplatin in human colon cancer cells.…”

mentioning

confidence: 99%

“…Quillaic-acid saponins of Quillaja saponaria and the steroid saponin digitonin of Digitalis purpurea were shown to promote the permeabilization of the plasma membrane in human leukemic H-L 60 cells [6] and in human ovarian carcinoma 2008 cells [7], respectively. In the course of our search for bioactive saponins from Caryophyllaceae, we describe here the effect of quillaicacid saponins, jenisseensosides A, B, C and D, (1 ± 4) (Chart 1) of two Silene species [8], [9] on the accumulation and cytotoxicity of cisplatin in human colon cancer cells.…”

mentioning

confidence: 99%

Saponins-Mediated Potentiation of Cisplatin Accumulation and Cytotoxicity in Human Colon Cancer Cells

Gaidi

Correia²,

Chauffert³

et al. 2002

Planta med

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The triterpene saponins jenisseensosides A, B, C, D were found to increase the accumulation and cytotoxicity of the anticancer agent cisplatin in human colon tumor cells. These compounds are glycosides of quillaic acid whose fucose residue was acylated by a trans- or cis-p methoxycinnamic acid. In contrast, other saponins derivatives without this acyl moiety were not found to potentiate the accumulation and cytotoxicity of cisplatin. These results suggested the importance of the acyl moiety for activity.

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“…Melvik et al demonstrated that electropermeabilisation of the cell membrane during DDP exposure increased sensitivity to DDP and that this was mediated by a 3-fold increase in DDP accumulation as measured by atomic absorption . Jekunen et al demonstrated that uptake could be enhanced by disrupting the cell membrane with heat or digitonin (Jekunen et al, 1992a). Exposure to 20 LM digitonin increased DDP accumulation 2-3-fold over control while exposure to 65°C increased the uptake 4-7-fold.…”

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confidence: 99%

Cellular accumulation of the anticancer agent cisplatin: A review

Gately

Howell²

1993

Br J Cancer

488

293

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Summary Acquired resistance to cisplatin (DDP) is a major clinical problem in the treatment of ovarian, testicular, and head and neck carcinomas; decreased accumulation of DDP is the most consistently observed alteration in resistant cells. It has been postulated that DDP enters the cell by passive diffusion based on the observations that DDP accumulation is proportional to the drug concentration, accumulation is not saturable, and that structural analogs of DDP do not inhibit accumulation. However, recent studies show that DDP accumulation can be specifically stimulated or inhibited by pharmacological agents and the activation of signal transduction pathways. This paper reviews the existing data on the mechanism of DDP accumulation and develops the postulate that some component of transport occurs through a gated ion channel.

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Modulation of cisplatin cytotoxicity by permeabilization of the plasma membrane by digitonin in vitro

Cited by 34 publications

References 18 publications

Combinations of Alkaloids Affecting Different Molecular Targets with the Saponin Digitonin Can Synergistically Enhance Trypanocidal Activity against Trypanosoma brucei brucei

Combinations of Alkaloids Affecting Different Molecular Targets with the Saponin Digitonin Can Synergistically Enhance Trypanocidal Activity against Trypanosoma brucei brucei

Saponins-Mediated Potentiation of Cisplatin Accumulation and Cytotoxicity in Human Colon Cancer Cells

Cellular accumulation of the anticancer agent cisplatin: A review

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