Differential expression and response to arsenic stress of MRPs and ASAN1 determine sensitivity of classical multidrug-resistant leukemia cells to arsenic trioxide

Leuk Res. 2016 Nov;50:116-122. doi: 10.1016/j.leukres.2016.10.003. Epub 2016 Oct 3.

Abstract

There is no cross-resistance between arsenic trioxide and conventional chemotherapeutics. Classical multi-drug resistant (MDR) cells remain sensitive to arsenic trioxide, which may even reverse the drug resistance. Arsenic trioxide is also effective in leukemias/tumors that persist despite conventional cytotoxic or targeted drugs. We obtained a highly arsenic-resistant MDR leukemic cell line, HL-60/RS, by exposing leukemic HL-60 cells to adriamycin selection. We compared the arsenic sensitivity, and the expression and responses to arsenic of the arsenic-related transporters, MRP1, MRP2, and ASNA1, in paired parent/arsenic-resistant HL-60/RS/HL-60 and arsenic-sensitive/parental K562/ADM/K562 cells. Expression levels of MRP1, MRP2, and ASNA1 were negatively correlated with cell sensitivities to arsenic trioxide, and ASNA1 expression notably was highest in HL-60/RS cells and lowest in K562/ADM cells. Expression levels of MRP1, MRP2, and ASNA1 were significantly enhanced in HL-60/RS cells and inhibited in K562/ADM cells by arsenic trioxide treatment, compared with their parental sensitive cells, in accord with the high-resistance of HL-60/RS cells and high-sensitivity of K562/ADM cells. In conclusion, the cross-resistance of conventional chemotherapeutics-resistant leukemic cells to arsenic trioxide is determined by both levels of MRP1, MRP2, and ASNA1, and also by the responses of these transporters to arsenic stress.

Keywords: ASNA1; Arsenic-resistance; Leukemia cell; MRP1; MRP2; Multi-drug resistance.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Arsenic / pharmacology
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Arsenite Transporting ATPases / analysis
  • Arsenite Transporting ATPases / drug effects*
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression / drug effects
  • HL-60 Cells
  • Humans
  • K562 Cells
  • Leukemia / drug therapy
  • Leukemia / pathology*
  • Multidrug Resistance-Associated Proteins / analysis
  • Multidrug Resistance-Associated Proteins / drug effects
  • Oxides / pharmacology*

Substances

  • Antineoplastic Agents
  • Arsenicals
  • GET3 protein, human
  • Multidrug Resistance-Associated Proteins
  • Oxides
  • multidrug resistance-associated protein 2
  • Arsenite Transporting ATPases
  • Arsenic
  • Arsenic Trioxide
  • multidrug resistance-associated protein 1