Unveiling (−)‐Englerin A as a Modulator of L‐Type Calcium Channels

Rodrigues, Tiago; Sieglitz, Florian; Somovilla, Víctor J.; Cal, Pedro M. S. D.; Galione, Antony; Corzana, Francisco; Bernardes, Gonçalo J. L.

doi:10.1002/ange.201604336

Cited by 11 publications

(6 citation statements)

References 29 publications

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“…Englerin A has been established to increase intracellular calcium levels [ 19 ] and this activity too may be modulated by ceramides. Though ceramides inhibit the L-type calcium channels [ 68 ], as englerin A was recently reported to do [ 26 ], it is unlikely that ceramides mediate this effect of englerin A. Modulation of L-type calcium channels by englerin A occurred at micromolar levels (Ki = 5.7 μM) while ceramides accumulate significantly in cc-RCC cells at nanomolar concentrations of englerin A. Ceramides were not found to modulate the TRPC4/5 channels and thus do not mediate englerin A activation of TRPC4/5 channels [ 71 ]. However, our collective results including the significant rise in ceramides in A498 cells in response to englerin A, as well as the many activities that ceramides and englerin A have in common, suggest that ceramides may mediate some of the actions of englerin A, especially in inducing ER stress, autophagy, and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Englerin A has also been shown to increase cytosolic calcium levels which may play a role in the decreased phosphorylation and activity of the oncoprotein, EWS-FLI1, in Ewing’s sarcoma [ 24 ]. Two other groups have reported that englerin A inhibits tumor cell growth by activating the transient receptor potential cation channel, subfamily C, member 4 (TRPC4) ion channel, while a third group reported that englerin A antagonized L-type calcium channels [ 21 , 25 , 26 ]. However, in at least two of these studies, the concentration of englerin A that was required to modulate these calcium channels was much higher than that required to kill renal carcinoma cells and other cells sensitive to the cytotoxic effects of englerin A.…”

Section: Introductionmentioning

confidence: 99%

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Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma

et al. 2017

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Renal cell carcinoma (RCC) is among the top ten most common forms of cancer and is the most common malignancy of the kidney. Clear cell renal carcinoma (cc-RCC), the most common type of RCC, is one of the most refractory cancers with an incidence that is on the rise. Screening of plant extracts in search of new anti-cancer agents resulted in the discovery of englerin A, a guaiane sesquiterpene with potent cytotoxicity against renal cancer cells and a small subset of other cancer cells. Though a few cellular targets have been identified for englerin A, it is still not clear what mechanisms account for the cytotoxicity of englerin A in RCC, which occurs at concentrations well below those used to engage the targets previously identified. Unlike any prior study, the current study used a systems biology approach to explore the mechanism(s) of action of englerin A. Metabolomics analyses indicated that englerin A profoundly altered lipid metabolism by 24 h in cc-RCC cell lines and generated significant levels of ceramides that were highly toxic to these cells. Microarray analyses determined that englerin A induced ER stress signaling and an acute inflammatory response, which was confirmed by quantitative PCR and Western Blot analyses. Additionally, fluorescence confocal microscopy revealed that englerin A at 25 nM disrupted the morphology of the ER confirming the deleterious effect of englerin A on the ER. Collectively, our findings suggest that cc-RCC is highly sensitive to disruptions in lipid metabolism and ER stress and that these vulnerabilities can be targeted for the treatment of cc-RCC and possibly other lipid storing cancers. Furthermore, our results suggest that ceramides may be a mediator of some of the actions of englerin A. Lastly, the acute inflammatory response induced by englerin A may mediate anti-tumor immunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma

et al. 2017

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“…We prioritized TRP channels for screening given the high prediction confidence and availability of assays for panel screening. Moreover, a privileged link between several members of the TRP channel family and natural products had been established 2,8,[19][20] . We further motivated screening of PL against TRP channels by processing the SPiDER output with a data visualization algorithm.…”

Section: Results and Discussion Self-organizing Maps Identify Trp Channels As Targets Of Piperlonguminementioning

confidence: 99%

“…Natural products provide ample opportunities to develop innovative medicines [1][2][3][4] . Yet, understanding their mechanisms of action remains a bottleneck to unlock their promise in drug discovery [5][6][7][8][9] . Chemoproteomics is a privileged approach to unveil new biology for molecules of therapeutic interest.…”

Section: Introductionmentioning

confidence: 99%

Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

et al. 2019

Self Cite

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The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of Piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Down-regulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumour grade, disease progression and poor prognosis. PL formulation for sustained local therapy using an implantable scaffold/hydrogel yielded extensive tumour abrogation in two murine models of orthotopic GBM by formulating PL for sustained local therapy using an implantable scaffold/hydrogel, together with long-term survival of treated animals. Furthermore, in primary tumour samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo. Our data establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel therapeutic vulnerabilities.

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“…Among these studied compounds, none indicated high selectivity for hCa v 1.3 [ 10 , 25 , 26 , 27 , 28 ] except some pyrimidine-2,4,6-triones (PYTs) reported recently by Kang et al In their research, the PYTs’ scaffold was identified as the first class of selective antagonists for hCa v 1.3. Especially, the compound (1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-trione) exhibited much higher IC 50 of hCa v 1.3 (1.7 μM) in contrast to hCa v 1.2 (1162 μM) [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Selectivity of L-Type Voltage-Gated Calcium Channels 1.3 for Pyrimidine-2,4,6-Triones Derivatives Based on Molecular Dynamics Simulation

Zhang

et al. 2020

Molecules

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Human Cav1.3 (hCav1.3) is of great interest as a potential target for Parkinson’s disease. However, common medications like dihydropyridines (DHPs), a kind of classic calcium channel blocker, have poor selectivity to hCav1.3 in clinical treatment, mainly due to being implicated in cardiovascular side-effects mediated by human Cav1.2 (hCav1.2). Recently, pyrimidine-2,4,6-triones (PYTs) have received extensive attention as prominent selective inhibitors to hCav1.3. In this study, we describe the selectivity mechanism of PYTs for hCav1.2 and hCav1.3 based on molecular dynamic simulation methods. Our results reveal that the van der Waals (vdW) interaction was the most important force affecting selectivity. Moreover, the hydrophobic interaction was more conducive to the combination. The highly hydrophobic amino acid residues on hCav1.3, such as V162 (IR1), L303 (IR2), M481 (IR3), and F484 (IR3), provided the greatest contributions in the binding free energy. On the other hand, the substituents of a halogen-substituted aromatic ring, cycloalkyl and norbornyl on PYTs, which are pertinent to the steric hindrance of the compounds, played core roles in the selectivity and affinity for hCav1.3, whereas strong polar substituents needed to be avoided. The findings could provide valuable information for designing more effective and safe medicines for Parkinson’s disease.

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Unveiling (−)‐Englerin A as a Modulator of L‐Type Calcium Channels

Cited by 11 publications

References 29 publications

Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma

Englerin A induces an acute inflammatory response and reveals lipid metabolism and ER stress as targetable vulnerabilities in renal cell carcinoma

Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression

Investigation of the Selectivity of L-Type Voltage-Gated Calcium Channels 1.3 for Pyrimidine-2,4,6-Triones Derivatives Based on Molecular Dynamics Simulation

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