Ubenimex Reverses MDR in Gastric Cancer Cells by Activating Caspase-3-Mediated Apoptosis and Suppressing the Expression of Membrane Transport Proteins

Biomed Res Int. 2019 Feb 20:2019:4390839. doi: 10.1155/2019/4390839. eCollection 2019.

Abstract

Gastric cancer (GC) is one of the most malignant tumors, accounting for 10% of deaths caused by all cancers. Chemotherapy is often necessary for treatment of GC; the FOLFOX regimen is extensively applied. However, multidrug resistance (MDR) of GC cells prevents wider application of this treatment. Ubenimex, an inhibitor of CD13, is used as an immune adjuvant to treat hematological malignancies. Here, we demonstrate that CD13 expression positively correlates with MDR development in GC cells. Moreover, Ubenimex reverses the MDR of SGC7901/X and MKN45/X cells and enhances their sensitivity to FOLFOX, in part by decreasing CD13 expression, which is accompanied by downregulation of Bcl-xl, Bcl-2, and survivin expression; increased expression of Bax; and activation of the caspase-3-mediated apoptotic cascade. In addition, Ubenimex downregulates expression of membrane transport proteins, such as P-gp and MRP1, by inhibiting phosphorylation in the PI3K/AKT/mTOR pathway to increase intracellular accumulations of 5-fluorouracil and oxaliplatin, a process for which downregulation of CD13 expression is essential. Therefore, the present results reveal a previously uncharacterized function of CD13 in promoting MDR development in GC cells and suggest that Ubenimex is a candidate for reversing the MDR of GC cells.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adult
  • Aged
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • CD13 Antigens / biosynthesis
  • CD13 Antigens / genetics
  • Caspase 3 / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Multiple / genetics
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Leucine / analogs & derivatives*
  • Leucine / pharmacology
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / biosynthesis
  • Multidrug Resistance-Associated Proteins / genetics
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • CD13 Antigens
  • CASP3 protein, human
  • Caspase 3
  • Leucine
  • ubenimex
  • multidrug resistance-associated protein 1