Cytotoxicity of Isoxazole Curcumin Analogs on Chronic Myeloid Leukemia-Derived K562 Cell Lines Sensitive and Resistant to Imatinib.

Despite curcumin (CUR) inhibiting cell proliferation in vitro by activating apoptotic cell death, its use in pharmacological therapy is hampered by poor solubility, low stability in biological fluids, and rapid removal from the body. Therefore, CUR-derivatives with better biological and chemical-physical characteristics are needed. The bis-ketone moiety of CUR strongly influences its stability in slightly alkaline solutions such as plasma. Here, we considered its replacement with isoxazole, beta-enamine, or oxime groups to obtain more stable derivatives. The evaluation of the chemical-physical characteristics showed that only of the isoxazole derivatives and had better potential than CUR in terms of bioavailability. The UV-visible spectrum analysis showed that derivatives and had better stability than CUR in solutions mimicking the biological fluids. When tested on a panel of cell lines, derivatives and had marked cytotoxicity (IC50 = 0.5 µM) compared with CUR only (IC50 = 17 µM) in the chronic myeloid leukemia (CML)-derived K562 cell line. The derivative was the more selective for CML cells. When administered at the average concentration found for CUR in the blood of patients, derivatives and had potent effects on cell cycle progression and apoptosis initiation, while CUR was ineffective. The apoptotic effect of derivatives and was associated with low necrosis. In addition, derivative was able to reverse drug resistance in K562 cells resistant to imatinib (IM), the reference drug used in CML therapy. The cytotoxicity of derivative on IM-sensitive and resistant cells was associated with upregulation of and expression, G2/M arrest, and triggering of apoptosis. In conclusion, derivative has chemical-physical characteristics and biological effects superior to CUR, which allow us to hypothesize its future use in the therapy of CML and CML forms resistant to IM, either alone or in combination with this drug.