Title : The enhanced cytotoxic effect of curcumin on leukemic stem cells via CD123-targeted nanoparticles
Abstract:
Treating acute myeloid leukemia (AML) remains challenging due to its resistance to drugs and high rates of relapse. One major mechanism of AML relapse is involved in the remaining leukemic stem cells (LSCs) in bone marrow. The prolonged residence of LSCs in the quiescent (G0) stage and the highly expressed P-glycoprotein drug transporter have been shown to allow them to evade chemotherapeutic drugs. LSCs are considered to be the root of chemotherapeutic drug resistance and relapse in AML patients. Hence, targeting LSCs emerges as a promising therapeutic target. CD123 is overexpressed in LSCs and leukemic blasts, but not in normal stem cells. CD123 thus represents a promising target molecule for drug delivery in order to specifically eradicate LSCs. In this study, we aimed to target and eliminate LSCs using CD123 as a key marker and curcumin as therapeutic agent. Curcumin, the active compound found in turmeric (Curcuma longa Linn.), is known for its ability to inhibit leukemic cell growth and is generally safe for humans in doses up to 8000 mg/day over three months. Unfortunately, its efficacy is limited by poor bioavailability, low water solubility, and rapid clearance from the body. To improve these limitations and enhance the selective eradication of LSCs, curcumin was encapsulated into nanoparticles to form nanocurcumin and then conjugated nanocurcumin with an anti-CD123 antibody (anti-CD123-Cur-NPs). The cytotoxicity of anti-CD123 Cur-NPs and curcumin-loaded nanoparticles (Cur-NPs) against KG-1a cells, serving as a model of leukemic stem cells, was investigated through the MTT assay. Our finding revealed that Cur-NPs and Cur-NPs-CD123 exhibited cytotoxic effects on KG-1a cells with the IC50 values of 74.20 ± 6.71 and 41.45 ± 5.49 µM, respectively. However, both Cur-NPs and anti-CD123-Cur-NPs did not show a cytotoxic effect on normal peripheral blood mononuclear cells (PBMCs). Moreover, anti-CD123-Cur-NPs treated KG-1a cells significantly enhanced the apoptotic cell number, when compared to Cur-NPs treated KG-1a cells. The higher uptake of anti-CD123-Cur-NPs in KG-1a cells was confirmed by using flow cytometry. In conclusion, the anti-CD123-Cur-NPs improved curcumin’s bioavailability and specific targeting of LSCs, suggesting that it is a promising drug delivery system for improving the therapeutic efficacy against AML.
