Assessing the anti-leukemic efficacy of a curcuminoid in cellular and animal models

Abstract

Leukemia ranks as the tenth most common cause of cancer-related deaths, and significant side effects often limit current treatments. Curcumin, a lipophilic polyphenol, has garnered considerable attention for its therapeutic potential in addressing various conditions, including inflammation, diabetes, aging, and cancer, particularly leukemia. In this study, ten novel curcuminoids were synthesized and structurally characterized for integrity and purity using spectral techniques. Cytotoxic evaluation against the MOLT-4, HEK, EL4, YAC1 and L1210 cell lines identified one compound, (3E,5E)-3,5-bis((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)piperidin-4-one (5e), to be potent, demonstrating superior cytotoxic activity compared to curcumin. Mechanistic studies revealed that treatment with 5e induced the production of reactive oxygen species (ROS), disrupted mitochondrial membrane potential, and promoted apoptosis, as confirmed by annexin-V-FITC/PI staining. Cell cycle analysis further showed significant accumulation in the sub-G₀/G₁ phase, consistent with apoptotic or necrotic cell death. In vivo studies using Dalton's Lymphoma models demonstrated that 5e effectively reduced tumor volume with minimal systemic toxicity. Western blot analyses confirmed activation of the intrinsic apoptotic pathway, with significant upregulation of cytochrome c and cleaved caspase-3. Moreover, 5e inhibited HDACs significantly in vitro, with activity greater than curcumin and comparable to trichostatin A, suggesting a target of anticancer action. Additionally, molecular docking studies suggested that 5e acts as a potential HDAC8 inhibitor, correlating with its enhanced anticancer activity. Collectively, these findings establish compound 5e as a promising curcuminoid analogue with potent cytotoxic and anti-proliferative effects against leukemia, highlighting its therapeutic potential.