Trypanocidal activity of salinomycin is due to sodium influx followed by cell swelling

Steverding, Dietmar; Sexton, Darren W.

doi:10.1186/1756-3305-6-78

Cited by 20 publications

(32 citation statements)

References 24 publications

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“…Perturbation of the cation gradient and/or content in infected versus normal RBCs or in the parasite cytosol may be responsible for the selective antimalarial effects of ionophores. A similar mechanism has been proposed to explain the activity of salinomycin against T. brucei and B. gibsoni (34,52) and the egress of T. gondii from host cells (59).…”

Section: Discussionmentioning

confidence: 97%

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Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

D’Alessandro

Corbett

Ilboudo

et al. 2015

Antimicrob Agents Chemother

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fThe drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC 50 ). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads.

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Section: Discussionmentioning

confidence: 97%

“…Recent reports highlighted their activity against Trypanosoma brucei, Toxoplasma gondii, and cytomegalovirus (33)(34)(35)(36). Considerable attention has been devoted recently to salinomycin and derivatives due to their selective activity against tumor stem cells (13,37,38).…”

Section: Discussionmentioning

confidence: 99%

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

D’Alessandro

Corbett

Ilboudo

et al. 2015

Antimicrob Agents Chemother

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“…Exploiting the synergy between oxidative and osmotic stress may be possible utilizing existing drugs. Thiol-modulating drugs like the clinically used anti-trypanosomal drug melarsoprol may synergize with ionophores like salinomycin, which kills trypanosomes via cytoplasmic swelling, resembling TLF-1 lysis (55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

Trypanosome Lytic Factor-1 Initiates Oxidation-stimulated Osmotic Lysis of Trypanosoma brucei brucei

Greene

Hajduk

2016

Journal of Biological Chemistry

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Human innate immunity against the veterinary pathogenTrypanosoma brucei brucei is conferred by trypanosome lytic factors (TLFs), against which human-infective T. brucei gambiense and T. brucei rhodesiense have evolved resistance. TLF-1 is a subclass of high density lipoprotein particles defined by two primate-specific apolipoproteins: the ion channel-forming toxin ApoL1 (apolipoprotein L1) and the hemoglobin (Hb) scavenger Hpr (haptoglobin-related protein). The role of oxidative stress in the TLF-1 lytic mechanism has been controversial. Here we show that oxidative processes are involved in TLF-1 killing of T. brucei brucei. The lipophilic antioxidant N,N-diphenyl-p-phenylenediamine protected TLF-1-treated T. brucei brucei from lysis. Conversely, lysis of TLF-1-treated T. brucei brucei was increased by the addition of peroxides or thiol-conjugating agents. Previously, the Hpr-Hb complex was postulated to be a source of free radicals during TLF-1 lysis. However, we found that the iron-containing heme of the Hpr-Hb complex was not involved in TLF-1 lysis. Furthermore, neither high concentrations of transferrin nor knock-out of cytosolic lipid peroxidases prevented TLF-1 lysis. Instead, purified ApoL1 was sufficient to induce lysis, and ApoL1 lysis was inhibited by the antioxidant DPPD. Swelling of TLF-1-treated T. brucei brucei was reminiscent of swelling under hypotonic stress. Moreover, TLF-1-treated T. brucei brucei became rapidly susceptible to hypotonic lysis. T. brucei brucei cells exposed to peroxides or thiol-binding agents were also sensitized to hypotonic lysis in the absence of TLF-1. We postulate that ApoL1 initiates osmotic stress at the plasma membrane, which sensitizes T. brucei brucei to oxidation-stimulated osmotic lysis.

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“…The large increase in cancer cases worldwide demonstrates the importance of research seeking more efficient drugs that improve patients' quality of life. Salinomycin is a promising anticancer drug and some mechanisms of action have been examined, including apoptosis induction (Fuchs et al 2009;Wang et al 2012;Zhou et al 2013;Fuchs et al 2010), DNA damage induction (Kim et al 2011), Pglycoprotein activity inhibition (Kim et al 2011), autophagy induction Jangamreddy et al 2013), oxidative stress induction ( (Ketola et al 2012;Zhou et al 2013), and trypanocidal activity (Steverding and Sexton 2013).…”

Section: Discussionmentioning

confidence: 99%

Salinomycin efficiency assessment in non-tumor (HB4a) and tumor (MCF-7) human breast cells

Niwa

D’Epiro

Marques

et al. 2016

Naunyn-Schmiedeberg's Arch Pharmacol

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The search for anticancer drugs has led researchers to study salinomycin, an ionophore antibiotic that selectively destroys cancer stem cells. In this study, salinomycin was assessed in two human cell lines, a breast adenocarcinoma (MCF-7) and a non-tumor breast cell line (HB4a), to verify its selective action against tumor cells. Real-time assessment of cell proliferation showed that HB4a cells are more resistant to salinomycin than MCF-7 tumor cell line, and these data were confirmed in a cytotoxicity assay. The half maximal inhibitory concentration (IC50) values show the increased sensitivity of MCF-7 cells to salinomycin. In the comet assay, only MCF-7 cells showed the induction of DNA damage. Flow cytometric analysis showed that cell death by apoptosis/necrosis was only induced in the MCF-7 cells. The increased expression of GADD45A and CDKN1A genes was observed in all cell lines. Decreased expression of CCNA2 and CCNB1 genes occurred only in tumor cells, suggesting G2/M cell cycle arrest. Consequently, cell death was activated in tumor cells through strong inhibition of the antiapoptotic genes BCL-2, BCL-XL, and BIRC5 genes in MCF-7 cells. These data demonstrate the selectivity of salinomycin in killing human mammary tumor cells. The cell death observed only in MCF-7 tumor cells was confirmed by gene expression analysis, where there was downregulation of antiapoptotic genes. These data contribute to clarifying the mechanism of action of salinomycin as a promising antitumor drug and, for the first time, we observed the higher resistance of HB4a non-tumor breast cells to salinomycin.

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Trypanocidal activity of salinomycin is due to sodium influx followed by cell swelling

Cited by 20 publications

References 24 publications

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

Trypanosome Lytic Factor-1 Initiates Oxidation-stimulated Osmotic Lysis of Trypanosoma brucei brucei

Salinomycin efficiency assessment in non-tumor (HB4a) and tumor (MCF-7) human breast cells

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