The thiophene α-terthienylmethanol isolated from Tagetes minuta inhibits 2 angiogenesis by targeting protein kinase C isozymes α and β2.

MARÍA C. LLORESN DE LOS RÍOS; PRISCILA A. LANZA; CECILIA L. BARBIERI; MARÍA L. GONZÁLEZ; MACARENA FUNES CHABÁN; GASTÓN SORIA; D. MARIANO A. VERA *; MARÍA CECILIA CARPINELLA *; MARÍA B. JORAY *

Frontiers in Pharmacology

Lausanne: Frontiers Media

Lugar: Lausanne; Año: 2022 vol. 13 p. 1007790 - 1007790

Background:Tumor angiogenesis is considered as a crucial pathologic feature ofcancer with a key role in multidrug resistance (MDR).Adverseeffects of the currently available drugs and the development ofresistance to these remain as the hardest obstacles to defeat. Objetive:Thiswork explores flora from Argentina as a source of new chemicalentities with antiangiogenic activity. Methods:Tubeformation assay using bovine aortic endothelial cells (BAECs) was theexperiment of choice to assess antiangiogenic activity. Theeffect of the pure compound in cell invasiveness was investigatedthrough the trans-well migration assay. The inhibitory effect of thepure compound on VEGFR2 and PKC isozymes α and β2 activation wasstudied by molecular and massive dynamic simulations. Cytotoxicity onperipheral blood mononuclear cells and erythrocyte cells wasevaluated by means of MTT and hemolysis assay, respectively. Insilico prediction of pharmacologicalproperties (ADME) and evaluation of drug-likeness features wereperformed using the SwissADME online tool.Results:Among the plants screened, Tagetesminuta,showedan outstanding effect with an IC50of33.6 ± 3.4 µg/mL.Bio-guided isolationyielded the terthiophene α-terthienylmethanolas its active metabolite.This compound inhibitedVEGF-induced tube formation with an IC50of 2.7 ± 0.4 µM and significantly impaired the invasiveness ofbovine aortic endothelial cells (BAECs) as well as of the highlyaggressive breast cancer cells, MDA-MB-231, when tested at 10 µM.DirectVEGFR-2 and PKC inhibition were both explored by means of massivemolecular dynamics simulations. The results obtainedvalidated the inhibitory effect on protein kinase C (PKC) isozymesαand β2as the main mechanism underlying its antiangiogenic activity.α-terthienylmethanolshowed no evidence of toxicity against peripheral blood mononuclearand erythrocyte cells. Conclusion:These findings support this thiophene as a promising antiangiogenicphytochemical to fight against several types of cancer mainly thosewith MDR phenotype.p { margin-bottom: 0.21cm; direction: ltr; color: #000000; line-height: 115%; text-align: left; orphans: 2; widows: 2; background: transparent }p.western { font-family: "Calibri", serif; font-size: 11pt; so-language: x-none }p.cjk { font-family: "Calibri"; font-size: 11pt; so-language: es-ES-u-co-trad }p.ctl { font-family: "Times New Roman"; font-size: 11pt; so-language: ar-SA }a:visited { color: #954f72; text-decoration: underline }a:link { color: #0563c1; text-decoration: underline }