Antileukemic Properties of Curcumin and Diarylpentanoid Analogue on Bcr-Abl-Positive Leukemic Cells

Introduction: The Philadelphia chromosome, a chromosomal translocation between chromosomes 9 and 22, is the most common cytogenetic abnormality in chronic myeloid leukemia (CML). The resulting gene product, Bcr-Abl protein, has constitutively active tyrosine kinase activity, which drives leukemogenesis. Curcumin is a natural bioactive compound isolated from the spice turmeric. It possesses a wide range of biological activities, including neuroprotective, antioxidative, anti-inflammatory, anti-diabetic, antimicrobial, and anticancer properties. However, the clinical application of curcumin is limited by its poor water solubility and bioavailability. Chemical modification of the curcumin keto-enol bridge can effectively improve its bioavailability without compromising its safety or biological properties. Our group has recently synthesized 1,5-bis(4hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (MS13), a diarylpentanoid analogue with a ketoenol bridge modification, which has demonstrated promising anticancer activity against cancers of several origins. Objectives: This study aims to determine the cytotoxicity and mode of cell death induced by curcumin and MS13 in Bcr-Abl-positive CML K562 cells, as well as the key pathways involved. Methods: The 24-, 48-, and 72-hour cytotoxicity of curcumin and MS13 on K562 CML cells was assessed using the MTT assay. Subsequently, the mode of cell death following 24-hour treatment was determined using the Annexin V-FITC/PI dual-labeling assay in conjunction with flow cytometry. The involvement of mitochondria and caspase activation was evaluated via mitochondrial TMRE staining and the caspase-GLO luminescent assay, respectively. Results: Curcumin and MS13 exhibited cytotoxicity against K562 cells in a time- and concentration-dependent manner. MS13 was more potent than curcumin at all treatment times, with lower half-maximal inhibitory concentration (IC50) values. Mechanistically, MS13 induced apoptosis but not necrotic cell death, with mitochondrial membrane potential loss and executioner caspase activation. Conclusion: MS13 is effective against CML and more potent than curcumin. It primarily induces apoptosis through mitochondrial membrane potential loss and executioner caspase activation. Further studies are needed to elucidate its molecular mechanisms of apoptosis.