Oleanolic and maslinic acid sensitize soft tissue sarcoma cells to doxorubicin by inhibiting the multidrug resistance protein MRP-1, but not P-glycoprotein.
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.
Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.
Victor Hugo
VH
Villar
Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.
Oliver
O
Vögler
Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.
Francisca
F
Barceló
Group of Cell Therapy and Tissue Engineering, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain.
Manuel
M
Gómez-Florit
Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain; Department of Hematology, University Hospital Son Espases, Palma de Mallorca, Spain.
Jordi
J
Martínez-Serra
Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain; Department of Oncology, University Hospital Son Espases, Palma de Mallorca, Spain.
Antònia
A
Obrador-Hevia
Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain; Department of Oncology, University Hospital Son Espases, Palma de Mallorca, Spain.
Javier
J
Martín-Broto
Instituto de la Grasa, Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain; CIBER:CB06/03 Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud, Carlos III (ISCIII), Spain.
Valentina
V
Ruiz-Gutiérrez
Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Palma de Mallorca, Spain; CIBER:CB06/03 Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud, Carlos III (ISCIII), Spain. Electronic address: regina.alemany@uib.es.
Regina
R
Alemany
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D009828:Oleanolic Acid / Q000494:pharmacology* / Q000031:analogs & derivatives; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D013584:Sarcoma, Synovial / Q000188:drug therapy; D014315:Triterpenes / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004317:Doxorubicin; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009828:Oleanolic Acid; D014315:Triterpenes; C412811:maslinic acid; C421109:multidrug resistance-associated protein 1
Doxorubicin; Drug resistance; MRP-1; Soft tissue sarcomas; Triterpenes