New Thalidomide-Resembling Dicarboximides Target ABC50 Protein and Show Antileukemic and Immunomodulatory Activities.
Marcin Janusz CieślakJulia Kaźmierczak-BarańskaKarolina Królewska-GolińskaMariola NapiórkowskaIga StukanUrszula WojdaBarbara NawrotPublished in: Biomolecules (2019)
We identified novel dicarboximides that were selectively cytotoxic towards human leukemia cells. Using chemical and biological methods, we characterized the biological activity, identified cellular protein targets and defined the mechanism of action of the test dicarboximides. The reported IC50 values (concentration required to reduce cell survival fraction to 50% of control) of selected dicarboximides were similar or lower than IC50 of registered anticancer drugs, for example cytarabine, sorafenib, irinotecan. Test compounds induced apoptosis in chronic myelogenous (K562) and acute lymphoblastic (MOLT-4) leukemia cells by activation of receptor and mitochondrial apoptotic pathways and increased the expression of proapoptotic genes (BAX, NOXA, HTRA2, TNFRSF10B, ESRRBL1). Selected dicarboximides displayed immunomodulatory activity and downregulated IKZF1 and IKZF3 transcription factors in K562 and MOLT-4 leukemia cells. ATP-binding cassette protein 50 (ABC50) was identified as a target for dicarboximides. Cancer cells with knocked down ABC50 showed increased resistance to dicarboximides. Based on the structure of dicarboximides and thalidomide, novel proteolysis-targeting chimeras (PROTACs) were synthesized and used as tools to downregulate ABC50 in leukemia cells.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- oxidative stress
- signaling pathway
- acute myeloid leukemia
- cell cycle arrest
- bone marrow
- cell death
- acute lymphoblastic leukemia
- endothelial cells
- protein protein
- high dose
- amino acid
- intensive care unit
- long non coding rna
- pi k akt
- cell proliferation
- acute respiratory distress syndrome
- dna binding