Plant extracts and betulin from Ligaria cuneifolia inhibit P-glycoprotein function in leukemia cells

JERONIMO LAIOLO; CECILIA BARBIERI; MARIANA B. JORAY; PRISCILA A. LANZA; SARA M. PALACIOS; D. M. A. VERA*; MARÍA C. CARPINELLA*

FOOD AND CHEMICAL TOXICOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2020 vol. 147 p. 111922 - 111922

0278-6915

Overexpressionof P-glycoprotein (P-gp), which is linked to multidrug resistance(MDR), is one of the underlying obstacles to the success ofchemotherapy asit reduces the efficacy of anticancer drugs and theside effects of these increase as a result of any increaseddose toachieve the therapeutic effect. Toidentify agents with P-gp inhibitory properties, ethanolextracts from 80 plants were screened for their ability to increaseintracellular doxorubicin-associated fluorescence, and the extractof Ligariacuneifolia wasfound to be the mosteffective. Its bioassay-guided isolation yielded the pentacyclictriterpene betulin as active agent. This efficiently inhibited P-gpmediated efflux, as demonstrated by the enhancement of theintracellular accumulation of doxorubicin and rhodamine 123 from1.56 µM in the P-gp overexpressing MDR leukemia cell,Lucena 1. Betulin was also able to render Lucena 1 sensitive to Doxfrom 0.39 µM. The docking studies revealed that betulin tightlybinds to a key region of the TMDs, with a binding mode overlappingone main site of doxorubicin and, more interestingly, emulating thesame contacts as tariquidar, as revealed by the per-residue energeticanalysis from molecular dynamics simulations. MTT assay usingperipheral blood mononuclear cells and hemolysis assay showed thatbetulin is devoid of toxicity.Thesefindings provide important evidence that betulin may be a safeand promising entity to be further investigated to develop agentsable to overcome P-gp-mediated MDR, resulting in a more effective andless toxic chemotherapy.p { margin-bottom: 0.21cm; direction: ltr; line-height: 108%; text-align: left; orphans: 2; widows: 2; background: transparent }p.western { font-size: 11pt }p.cjk { font-size: 11pt }a:link { color: #0000ff; text-decoration: underline }