Salinomycin derivatives exhibit activity against primary acute lymphoblastic leukemia (ALL) cells in vitro

Biomed Pharmacother. 2018 Mar:99:384-390. doi: 10.1016/j.biopha.2018.01.081.

Abstract

Salinomycin (SAL) and monensin (MON) are polyether ionophore antibiotics commonly used in veterinary medicine. They are known from their anti-cancer activity against various types of cancer cells, including those that display multi-drug resistance as well as cancer stem cells. In order to increase the biological activity profile and reduce toxicity against normal cells, while retaining the activities in the micromolar range, a library of ester and amide derivatives of SAL was synthesized and previously reported. In this paper, we examined the activity of SAL, its ten derivatives, and MON on primary acute lymphoblastic leukemia cells. MON and six SAL derivatives were more potent than SAL in cell viability assays. Further, selected active SAL analogs induced characteristics of apoptotic cell death and increased expression of p53. Moreover, SAL acted synergistically with the Bcl-2 inhibitor ABT-263, whereas 2,2,2-trifluoroethyl ester, the most active analog of SAL, antagonized ABT-263, suggesting possible differences in molecular mechanism.

Keywords: Acute lymphoblastic leukemia; Anti-cancer activity; Monensin; Salinomycin.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology
  • Amides / therapeutic use
  • Aniline Compounds / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Fragmentation / drug effects
  • Esters / chemistry
  • Esters / pharmacology
  • Esters / therapeutic use
  • Humans
  • Monensin / pharmacology
  • Monensin / therapeutic use
  • Poly(ADP-ribose) Polymerases / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrans / chemistry
  • Pyrans / pharmacology
  • Pyrans / therapeutic use*
  • Sulfonamides / pharmacology
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Amides
  • Aniline Compounds
  • Esters
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrans
  • Sulfonamides
  • Tumor Suppressor Protein p53
  • salinomycin
  • Monensin
  • Poly(ADP-ribose) Polymerases
  • navitoclax