title: 3β-Acetyl tormentic acid reverts MRP1/ABCC1 mediated cancer resistance through modulation of intracellular levels of GSH and inhibition of GST activity.
abstract: ABC transporter overexpression is an important mechanism of multidrug resistance (MDR) and one of the main obstacles to successful cancer treatment. As these proteins actively remove chemotherapeutics from the tumor cells, the pharmacological inhibition of their activity is a possible strategy to revert drug resistance. Moreover, the ability of MDR inhibitors to sensitize resistant cells to conventional drugs is important for their clinical use. Evidence has shown that the multidrug resistance protein 1 (MRP1/ABCC1) is a negative prognostic marker in patients with lung, gastric, or breast cancers or neuroblastoma. Previous data have shown that 3β-acetyl tormentic acid (3ATA) inhibits the transport activity of the protein MRP1/ABCC1. In this study, we evaluated the ability of 3ATA to sensitize an MDR cell line (GLC4/ADR), which overexpresses MRP1, and investigated the anti-MRP1 mechanisms activated by 3ATA. The results showed that 3ATA is able to reverse the resistance of the MDR cell line to doxorubicin and vincristine, two drugs that are commonly used in cancer chemotherapy. Regarding the sensitizing mechanism induced by 3ATA, this work shows that the triterpene does not modulate the expression of MRP1/ABCC1 but is able to reduce total intracellular glutathione (GSH) levels and decrease the activity of glutathione-s-transferase (GST), the enzyme responsible for the glutathione conjugation of xenobiotics. Together, these results show that 3ATA sensitizes the MDR cell line overexpressing MRP1/ABCC1 to antineoplastic drugs and that this effect is mediated by the modulation of intracellular levels of GSH and GST activity.
authors.affiliation: Laboratory of Cellular Immunology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21949-900, RJ, Brazil. Electronic address: gleicegr@gmail.com.
authors.forename: Gleice da Graça
authors.initials: Gda G
authors.lastname: Rocha
authors.affiliation: Natural Products Research Center, Federal University of Rio de Janeiro, Rio de Janeiro 21949-900, RJ, Brazil. Electronic address: roroliveira@uenf.br.
authors.forename: Rodrigo Rodrigues
authors.initials: RR
authors.lastname: Oliveira
authors.affiliation: Natural Products Research Center, Federal University of Rio de Janeiro, Rio de Janeiro 21949-900, RJ, Brazil. Electronic address: makaplan@hotmail.com.
authors.forename: Maria Auxiliadora Coelho
authors.initials: MA
authors.lastname: Kaplan
authors.affiliation: Laboratory of Cellular Immunology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21949-900, RJ, Brazil. Electronic address: cerli@biof.ufrj.br.
authors.forename: Cerli Rocha
authors.initials: CR
authors.lastname: Gattass
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000502:physiology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005978:Glutathione; D005982:Glutathione Transferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014315:Triterpenes; C007695:euscaphic acid; C421109:multidrug resistance-associated protein 1
keywords: 3β-acetyl tormentic acid; Cancer; MRP1/ABCC1 inhibitor; Multidrug resistance reversal; Triterpenes