Englerin A Selectively Induces Necrosis in Human Renal Cancer Cells

Abstract

The number of renal cancers has increased over the last ten years and patient survival in advanced stages remains very poor. Therefore, new therapeutic approaches for renal cancer are essential. Englerin A is a natural product with a very potent and selective cytotoxicity against renal cancer cells. This makes it a promising drug candidate that may improve current treatment standards for patients with renal cancers in all stages. However, little is known about englerin A's mode of action in targeting specifically renal cancer cells. Our study is the first to investigate the biological mechanism of englerin A action in detail. We report that englerin A is specific for renal tumor cells and does not affect normal kidney cells. We find that englerin A treatment induces necrotic cell death in renal cancer cells but not in normal kidney cells. We further show that autophagic and pyroptotic proteins are unaffected by the compound and that necrotic signaling in these cells coincided with production of reactive oxygen species and calcium influx into the cytoplasm. As the first study to analyze the biological effects of englerin A, our work provides an important basis for the evaluation and validation of the compound's use as an anti-tumor drug. It also provides a context in which to identify the specific target or targets of englerin A in renal cancer cells.

Metabolic alterations in renal cell carcinoma

“…Efforts are directed at defining the therapeutic role of englerin A, which activates protein kinase C-h and the transcription factor heat shock factor 1 (HSF1), inducing an insulin-resistant phenotype starving cells of glucose while simultaneously promoting glucose dependence [72,73].…”

Synthesis and Biological Evaluation of New (−)‐Englerin Analogues

“…18,19,21,30,31 Therefore, to take advantage of the different advanced intermediates 6a–c generated through our synthetic route, our strategy consisted in adding these substituents to the oxatricyclic intermediates with different levels of unsaturation. In this way, we could have a ready direct access to a set of analogues with great structural diversification.…”

Englerins: A Comprehensive Review

“…58,62,65 The unique cell biology of Ewing’s sarcoma is selectively affected by englerin A through decreased phosphorylation of the chimeric EWS-FLI1 transcription factor. 63 …”

“…58 An increase in intracellular calcium concentration was found after englerin exposure, and this was interpreted as evidence for a necrotic mechanism. 58 …”

“…62 The effect on calcium was congruent with Ramos’s previous reports and with work later reported at NCI. 58,63 The effect was blocked by the TRPC4 inhibitor ML204, 64 and cells were rescued from englerin A cytotoxicity by EGTA, a cell-impermeable calcium chelator. 62 GPCR-stimulated activation of TRPC4/5 channels was ruled out by blockade of GPCR signaling by a stable guanosine diphosphate analogue.…”