DPOFA, a Cl-/HCO3
-exchanger antagonist, stimulates fluid absorption across basolateral surface of the retinal pigment epithelium

Iserovich, P.; Qin, Qiong; Petrukhin, Konstantin

doi:10.1186/1471-2415-11-33

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…Thus, sphaeropsidin A together with NKCC1 inhibitor ethacrynic acid [52], WNK-SPAK/OSR1-NKCC1/NKCC2 pathway inhibitor STOCK1S-50699 [53] and Cl − /HCO 3 − exchanger antagonist DPOFA [54] contain reactive Michael acceptor functionalities (Fig. 10, highlighted in blue).…”

Section: Discussionmentioning

confidence: 99%

Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

Mathieu

Chantôme

Lefranc

et al. 2015

Cell. Mol. Life Sci.

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Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 μM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl− and the decreased HCO3− concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na–K–2Cl electroneutral cotransporter or Cl−/HCO3− anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

Mathieu

Chantôme

Lefranc

et al. 2015

Cell. Mol. Life Sci.

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“…To a smaller extent, inhibition of basal Na þ -HCO À 3 (1 : 2) co-transporter and anion exchanger also increases the rate of fluid removal from the SRS. The effect of the anion exchanger on water flux has been confirmed experimentally by Iserovich et al [40].…”

mentioning

confidence: 70%

Fluid and solute transport across the retinal pigment epithelium: a theoretical model

Dvoriashyna

Foss

Gaffney

et al. 2020

J. R. Soc. Interface.

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The retina is composed of two main layers—the neuroretina and the retinal pigment epithelium (RPE)—that are separated by a potential gap termed the sub-retinal space (SRS). Accumulation of fluid in the SRS may result in a retinal detachment. A key function of the RPE is to prevent fluid accumulation in the SRS by actively pumping fluid from this space to the choroid. We have developed a mathematical model of this process that incorporates the transport of seven chemical species: Na + , K + , Cl − , HCO 3 − , H + , CO 2 and H 2 CO 3 . This allows us to estimate solute and water fluxes and to understand the role of the different membrane ion channels. We have performed a global sensitivity analysis using the extended Fourier amplitude sensitivity test to investigate the relative importance of parameters in generating the model outputs. The model predicts that flow across the RPE is driven by an osmotic gradient in the cleft gap between adjacent cells. Moreover, the model estimates how water flux is modified in response to inhibition of membrane ion channels and carbonic anhydrase (CA). It provides a possible explanation for how CA inhibitors, which are used clinically to prevent fluid accumulation in the SRS, may be acting.

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Mouse retinal pigment epithelial cells exhibit a thiocyanate-selective conductance

Cao

Pattnaik

Hughes

2018

American Journal of Physiology-Cell Physiology

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The basolateral membrane anion conductance of the retinal pigment epithelium (RPE) is a key component of the transepithelial Cl transport pathway. Although multiple Cl channels have been found to be expressed in the RPE, the components of the resting Cl conductance have not been identified. In this study, we used the patch-clamp method to characterize the ion selectivity of the anion conductance in isolated mouse RPE cells and in excised patches of RPE basolateral and apical membranes. Relative permeabilities ( P/ P) calculated from reversal potentials measured in intact cells under bi-ionic conditions were as follows: SCN >> ClO > [Formula: see text] > I > Br > Cl >> gluconate. Relative conductances ( G/ G) followed a similar trend of SCN >> ClO > [Formula: see text] > I > Br ≈Cl >> gluconate. Whole cell currents were highly time-dependent in 10 mM external SCN, reflecting collapse of the electrochemical potential gradient due to SCN accumulation or depletion intracellularly. When the membrane potential was held at -120 mV to minimize SCN accumulation in cells exposed to 10 mM SCN, the instantaneous current reversed at -90 mV, revealing that P/ P is approximately 500. Macroscopic current recordings from outside-out patches demonstrated that both the basolateral and apical membranes exhibit SCN conductances, with the basolateral membrane having a larger SCN current density and higher relative permeability for SCN. Our results suggest that the RPE basolateral and apical membranes contain previously unappreciated anion channels or electrogenic transporters that may mediate the transmembrane fluxes of SCN and Cl.

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DPOFA, a Cl-/HCO3 -exchanger antagonist, stimulates fluid absorption across basolateral surface of the retinal pigment epithelium

Cited by 3 publications

References 24 publications

Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

Fluid and solute transport across the retinal pigment epithelium: a theoretical model

Mouse retinal pigment epithelial cells exhibit a thiocyanate-selective conductance

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