Oleanolic and maslinic acid sensitize soft tissue sarcoma cells to doxorubicin by inhibiting the multidrug resistance protein MRP-1, but not P-glycoprotein

Victor Hugo Villar, Oliver Vögler, Francisca Barceló, Manuel Gómez-Florit, Jordi Martínez-Serra, Antònia Obrador-Hevia, Javier Martín-Broto, Valentina Ruiz-Gutiérrez, Regina Alemany

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23 Citations (Scopus)

Abstract

The pentacyclic triterpenes oleanolic acid (OLA) and maslinic acid (MLA) are natural compounds present in many plants and dietary products consumed in the Mediterranean diet (e.g., pomace and virgin olive oils). Several nutraceutical activities have been attributed to OLA and MLA, whose antitumoral effects have been extensively evaluated in human adenocarcinomas, but little is known regarding their effectiveness in soft tissue sarcomas (STS). We assessed efficacy and molecular mechanisms involved in the antiproliferative effects of OLA and MLA as single agents or in combination with doxorubicin (DXR) in human synovial sarcoma SW982 and leiomyosarcoma SK-UT-1 cells. As single compound, MLA (10-100 μM) was more potent than OLA, inhibiting the growth of SW982 and SK-UT-1 cells by 70.3 ± 1.11% and 68.8 ± 1.52% at 80 μM, respectively. Importantly, OLA (80 μM) or MLA (30 μM) enhanced the antitumoral effect of DXR (0.5-10 μM) by up to 2.3-fold. On the molecular level, efflux activity of the multidrug resistance protein MRP-1, but not of the P-glycoprotein, was inhibited. Most probably as a consequence, DXR accumulated in these cells. Kinetic studies showed that OLA behaved as a competitive inhibitor of substrate-mediated MRP-1 transport, whereas MLA acted as a non-competitive one. Moreover, none of both triterpenes induced a compensatory increase in MRP-1 expression. In summary, OLA or MLA sensitized cellular models of STS to DXR and selectively inhibited MRP-1 activity, but not its expression, leading to a higher antitumoral effect possibly relevant for clinical treatment.

Original languageEnglish
Pages (from-to)429-38
Number of pages10
JournalThe Journal of nutritional biochemistry
Volume25
Issue number4
DOIs
Publication statusPublished - Apr 2014

Keywords

  • ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
  • Antineoplastic Agents, Phytogenic/pharmacology
  • Cell Line, Tumor/drug effects
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Doxorubicin/pharmacokinetics
  • Drug Resistance, Neoplasm/drug effects
  • Glutathione/metabolism
  • Humans
  • Multidrug Resistance-Associated Proteins/antagonists & inhibitors
  • Oleanolic Acid/pharmacology
  • Sarcoma/drug therapy
  • Sarcoma, Synovial/drug therapy
  • Triterpenes/pharmacology

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