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Activity of Single and Double‐modified Salinomycin Analogs against Primary Acute Lymphoblastic Cells In Vitro
Author(s) -
Urbaniak Alicja Joanna,
Delgado Magdalena Rose,
Antoszczak Michał,
Borgström Björn,
Strand Daniel,
Huczyñski Adam,
Chambers Timothy C.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.836.15
Subject(s) - salinomycin , chemistry , in vitro , cancer cell , pharmacology , apoptosis , viability assay , cell culture , ionophore , cancer , stereochemistry , biochemistry , medicine , biology , antibiotics , membrane , genetics
Salinomycin ( SAL ) and monensin ( MON ) are polyether ionophore antibiotics 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 novel SAL analogs has been synthesized. This included esters and amides single‐modified in C1 position as well as double‐modified derivatives additionally acylated in the C20 position (Fig. 1). The aim of the study was to evaluate the activity of newly synthesized SAL derivatives (12 single‐modified and 12 double‐modified) towards primary acute lymphoblastic leukemia cells. MON (IC 50 = 1.2 ± 0.8 μM) and nine SAL derivatives (IC 50 in the range of 1.2 ± 0.02 to 1.9 ± 0.7 μM) were more potent than SAL (IC 50 = 2.4 ± 0.7 μM) in cell viability assays. Moreover, the most potent SAL analogs induced characteristics of apoptotic cell death and increased expression of p53. In further studies, 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. This is intriguing and suggests that the parent compound may differ mechanistically from its derivatives. The present findings indicate that SAL derivatives constitute promising lead compounds for targeting acute lymphoblastic leukemia. Further study and development of these novel cancer therapeutics with potential clinical application is warranted. Support or Funding Information TCC acknowledges support from Arkansas Breast Cancer Research Program and Chancellors Circle Award from the UAMS College of Medicine. MA thanks the Polish Science Centre (NCN) for financial support by grant SONATA (2016/23/D/ST5/00242) and fellowship ETIUDA (2014/12/T/ST5/00710). We thank the Swedish Research Council, and the Cancer Foundation for funding. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .