Medeiros, Hyllana C. D.
Ferraz, Leticia S.
Costa, Claudia A.
Moraes, Vivian W. R.
Paredes-Gamero, Edgar Julian
Tersariol, Ivarne L. S.
Total Authors: 8
 Fed Univ ABC, Ctr Nat & Human Sci, UFABC, CCNH, Ave Estados 5001, Bloco A, Torre 3, Sala 623, BR-09021058 Santo Andre, SP - Brazil
 Univ Mogi das Cruzes, Interdisciplinary Ctr Biochem Invest, CIIB, Mogi das Cruzes, SP - Brazil
 Scripps Res Inst, Dept Mol Med, La Jolla, CA - USA
 Univ Fed Mato Grosso do Sul, Sch Pharmaceut Sci, UFMS, Campo Grande, MS - Brazil
 Univ Fed Sao Paulo, Sao Paulo Sch Med, Dept Biochem, Unifesp, Sao Paulo, SP - Brazil
Total Affiliations: 5
JAN 5 2020.
Web of Science Citations:
Relapse and drug resistance is still major challenges in the treatment of leukemia. Promethazine, an antihistaminic phenothiazine derivative, has been used to prevent chemotherapy-induced emesis, although there is no report about its antitumor potential. Thus, we evaluated the promethazine cytotoxicity against several leukemia cells and the underlying mechanisms were investigated. Promethazine exhibited potent and selective cytotoxicity against all leukemia cell types in vitro at clinically relevant concentrations. Philadelphia positive chronic myeloid leukemia (CML) K562 cells were the most sensitive cell line. The cytotoxicity of promethazine in these cells was triggered by the activation of AMPK and inhibition of PI3K/AKT/mTOR pathway. The subsequent downstream effects were NOXA increase, MCL-1 decrease, and Beclin-1 activation, resulting in autophagy-as-sociated apoptosis. These data highlight targeting autophagy may represent an interesting strategy in CML therapy, and also the antitumor potential of promethazine by acing in AMPK and PI3K/AKT/mTOR signaling pathways. Since this drug is currently used with relative low side effects, its repurposing may represent a new therapeutic opportunity for leukemia treatment. (AU)