Synthetic Prodiginine Obatoclax (GX15‐070) and Related Analogues: Anion Binding, Transmembrane Transport, and Cytotoxicity Properties

Greñu, Borja Díaz de; Hernández, Paulina Iglesias; Espona, Margarita; Quiñonero, David; Light, Mark E.; Torroba, Tomás; Pérez‐Tomás, Ricardo; Quesada, Roberto

doi:10.1002/chem.201101547

Cited by 108 publications

(56 citation statements)

References 45 publications

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“…This process might be mechanistically explained by the notion that Obatoclax has also been shown, at least in vitro , to possess anion carrier activity and to be able to function as an antiport for Cl − and HCO 3 − in model liposomes [41]. This mechanism might thus lead to the efflux of Cl − from lysosomes, thus reducing the activity of the V-ATPase by increasing voltage across the lysosomal membrane [42], and to an influx of HCO 3 − , causing the rapid increase of lysosomal pH we have observed in cells exposed to Obatoclax.…”

Section: Discussionmentioning

confidence: 99%

Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis

et al. 2016

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Poorly differentiated and anaplastic thyroid carcinomas are very aggressive, almost invariably lethal neoplasms for which no effective treatment exists. These tumors are intrinsically resistant to cell death, even when their driver oncogenic signaling pathways are inhibited.We have undertaken a detailed analysis, in mouse and human thyroid cancer cells, of the mechanism through which Obatoclax, a pan-inhibitor of the anti-apoptotic proteins of the BCL2 family, effectively reduces tumor growth in vitro and in vivo.We demonstrate that Obatoclax does not induce apoptosis, but rather necrosis of thyroid cancer cells, and that non-transformed thyroid cells are significantly less affected by this compound. Surprisingly, we show that Obatoclax rapidly localizes to the lysosomes and induces loss of acidification, block of lysosomal fusion with autophagic vacuoles, and subsequent lysosomal permeabilization. Notably, prior lysosome neutralization using different V-ATPase inhibitors partially protects cancer cells from the toxic effects of Obatoclax. Although inhibition of autophagy does not affect Obatoclax-induced cell death, selective down-regulation of ATG7, but not of ATG5, partially impairs Obatoclax effects, suggesting the existence of autophagy-independent functions for ATG7. Strikingly, Obatoclax killing activity depends only on its accumulation in the lysosomes, and not on its interaction with BCL2 family members.Finally, we show that also other lysosome-targeting compounds, Mefloquine and LLOMe, readily induce necrosis in thyroid cancer cells, and that Mefloquine significantly impairs tumor growth in vivo, highlighting a clear vulnerability of these aggressive, apoptosis-resistant tumors that can be therapeutically exploited.

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Section: Discussionmentioning

confidence: 99%

Obatoclax kills anaplastic thyroid cancer cells by inducing lysosome neutralization and necrosis

et al. 2016

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“…[90][91][92] The anion binding and transport properties of obatoclax (154a, a synthetic prodiginin that is currently in clinical trials as an anticancer drug) have been investigated by Quesada and co-workers, with the aim of discovering the mechanism of its anticancer activity. 93 Variations of the pyrrole substituents resulted in a series of compounds (154a,b,c-157) capable of transporting chloride and bicarbonate anions across synthetic POPC bilayers, via an antiport mechanism of transport. Compound 154b showed the highest transport ability for the chloride-bicarbonate antiport process (EC 50,290s = 0.18 mM).…”

Section: Transmembrane Anion Transportmentioning

confidence: 99%

Anion receptor chemistry: highlights from 2011 and 2012

et al. 2014

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“…93 Variations of the pyrrole substituents resulted in a series of compounds (154a,b,c-157) capable of transporting chloride and bicarbonate anions across synthetic POPC bilayers, via an antiport mechanism of transport. Compound 154b showed the highest transport ability for the chloride-bicarbonate antiport process (EC 50,290s = 0.18 mM).…”

Section: -92mentioning

confidence: 99%