An evaluation of the mechanism of action of pentamidine isethionate

Bornstein, Richard S.; Yarbro, John W.

doi:10.1002/jso.2930020412

Cited by 20 publications

(6 citation statements)

References 11 publications

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“…Pentamidine can bind to nucleosides from nucleic acids, ATP and ADP in vitro [21]. This observation is consistent with the previous demonstration that pentamidine interferes with DNA, RNA and protein synthesis [22,23] and inhibits thymidylate synthetase [24]. No protective effect of high glucose or nicotinamide concentrations on the/3-cell function was observed in the present experimental sets, although some protection may exist for shorter exposure times, as regards eytotoxieity (D. Pipeleers, unpublished observations).…”

Section: Discussionsupporting

confidence: 90%

Functional and morphological modifications induced in rat islets by pentamidine and other diamidines in vitro

et al. 1985

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The antiprotozoal drug pentamidine can be toxic to islet cells in vivo and in vitro. Rat islets were exposed to pentamidine (mesylate and isethionate salts) and six other structurally related diamidines. The beta-cell response to arginine + theophylline was suppressed by pentamidine (10(-2) mmol/l) while the glucagon and somatostatin secretions persisted. All diamidines tested suppressed the beta-cell function, with a log-dose-response proportionality, the mesylate compound being more potent than pentamidine isethionate, and the lipophilic analogs more than the hydrosoluble diamidines. Electron microscopy revealed distinct morphological alterations in islets exposed to pentamidine, the intensity of these changes being dose-and time-dependent, and the beta cells more severely damaged than the non-beta cells. 51Cr-labelled islet cells and RIN 5 F cells consistently appeared more sensitive to pentamidine cytotoxicity than rat fibroblasts, myeloma cells and hepatocytes. The pentamidine-induced suppression of beta-cell function was not, in conditions tested, affected by the presence of nicotinamide and the hexose concentration in the medium. The kinetics of islet damage were slower than those of streptozotocin and alloxan-induced islet damage. The present study confirms that pentamidine is selectively toxic to islet beta cells, with some features distinct from the alloxan and streptozotocin toxicities to these cells. The mechanism of this process and its precipitating factors in vivo need clarification.

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Section: Discussionsupporting

confidence: 90%

Functional and morphological modifications induced in rat islets by pentamidine and other diamidines in vitro

et al. 1985

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“…Pentamidin is capable of binding to the minor groove of double-strand DNA but not single-strand DNA and inhibits protein synthesis, DNA synthesis and the activity of endo-exonuclease in Pneumocystis carinii [24]. Further, DNA and protein synthesis in human tumor also decreased by pentamidine treatment [25]. Recently, it was reported that pentamidine also inhibited human endo-exonuclease activity in vitro and induced cell death in several tumor cells efficiently [26].…”

Section: Introductionmentioning

confidence: 99%

Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation

et al. 2010

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BackgroundMRE11 is an important nuclease which functions in the end-resection step of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). As MRE11-deficient ATLD cells exhibit hyper radio-sensitivity and impaired DSB repair, MRE11 inhibitors could possibly function as potent radio-sensitizers. Therefore, we investigated whether a bisbenzamidine derivative, pentamidine, which can inhibit endoexonuclease activity, might influence DSB-induced damage responses via inhibition of MRE11.ResultsWe first clarified that pentamidine inhibited MRE11 nuclease activity and also reduced ATM kinase activity in vitro. Pentamidine increased the radio-sensitivity of HeLa cells, suggesting that this compound could possibly influence DNA damage response factors in vivo. Indeed, we found that pentamidine reduced the accumulation of γ-H2AX, NBS1 and phospho-ATM at the sites of DSBs. Furthermore, pentamidine decreased HR activity in vivo. Pentamidine was found to inhibit the acetylation of histone H2A which could contribute both to inhibition of IR-induced focus formation and HR repair. These results suggest that pentamidine might exert its effects by inhibiting histone acetyltransferases. We found that pentamidine repressed the activity of Tip60 acetyltransferase which is known to acetylate histone H2A and that knockdown of Tip60 by siRNA reduced HR activity.ConclusionThese results indicate that inhibition of Tip60 as well as hMRE11 nuclease by pentamidine underlies the radiosensitizing effects of this compound making it an excellent sensitizer for radiotherapy or chemotherapy.

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“…Consequently, the effect of Pe in the release of cytokines from AM may be a nonspecific effect on RNA synthesis since 18s rRNA, which has a longer half life, was not affected. Indeed, Bornstein and Yarbro [ 3 ] found that Pe inhibited incorporation of thymidine and uridine into DNA and RNA, and also inhibited protein synthesis in a mouse ascites tumor line. In their studies the minimum effective dose was 1 mg/mL, which is 200 times higher than the concentration affecting mRNA expression in human AM.…”

Section: Discussionmentioning

confidence: 98%

Effect of Pentamidine on Cytokine (IL-β, TNFα, IL-6) Production by Human Alveolar Macrophages in Vitro

Quay

Rosenthal

Becker

1993

Experimental Lung Research

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Pentamidine (Pe) is an aromatic diamidine drug used clinically to treat Pneumocystis carinii pneumonia by aerosol inhalation. Nothing has been reported about the effects of this drug on human alveolar macrophage (AM) properties. In this study AM were exposed in vitro to various concentrations of Pe (10(-4)-10(-6) M) alone or in combination with bacterial endotoxin (LPS). Supernatants were collected at 3, 6, and 24 h and assayed for secreted IL-1 beta, IL-6, and TNF alpha. While the drug did not induce release of these cytokines, LPS-induced secretion of all three cytokines was inhibited by Pe in a dose-dependent manner. At the most effective Pe dose, 10(-5) M, AM viability (as determined by trypan blue dye exclusion) was reduced by 14% at 24 h, while no effect on viability was seen at lower concentrations. mRNA expression of all three cytokines was examined by PCR and Northern analysis to establish if the decrease in cytokine secretion was determined on a pre- or post-translational level. Reduced steady-state mRNA levels were found as early as 3 h after LPS stimulation, with Pe concentrations corresponding to those that decreased cytokine secretion. At the later time points, Pe also inhibited beta-actin, ornithine decarboxylase, and GAPDH mRNA expression, indicating that pentamidine had a general toxic effect on mRNA transcription in the macrophages. It is concluded that Pe, at pharmaceutically relevant concentrations and with apparent low cytotoxicity as determined by dye uptake, nonspecifically inhibits cytokine production by a toxic effect on transcriptional events.

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An evaluation of the mechanism of action of pentamidine isethionate

Cited by 20 publications

References 11 publications

Functional and morphological modifications induced in rat islets by pentamidine and other diamidines in vitro

Functional and morphological modifications induced in rat islets by pentamidine and other diamidines in vitro

Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation

Effect of Pentamidine on Cytokine (IL-β, TNFα, IL-6) Production by Human Alveolar Macrophages in Vitro

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