Deciphering the Anti-Cancer Efficacy of the Combination of Small-Molecule Inhibitor KAN0438757 and Curcumin in Lung...

Lung cancer is among the most aggressive malignancies, with the highest incidence and mortality rates worldwide. Standard treatments include surgery, radiotherapy, and chemotherapy; however, chemoresistance often develops, reducing therapeutic efficacy. Combination therapy offers a promising strategy to enhance drug effectiveness and overcome resistance. In lung cancer, the increased energy demands within cells result in a marked rise in the expression of PFKFB3, a regulatory protein involved in the glucose metabolic pathway. The small-molecule inhibitor KAN0438757, recognized as a novel PFKFB3 inhibitor, is significant in targeted therapy due to its essential role in the DNA damage response mechanism in cancer cells. Curcumin, the primary bioactive compound found in the rhizomes of Curcuma longa, has demonstrated a variety of biological functions and anticancer properties. This study aimed to evaluate the anticancer effects of KAN0438757 in combination with curcumin in lung cancer cells. Evaluation of cell viability and IC₅₀ values (KAN0438757: A549, 41.13 µM; H1299, 53.74 µM; Curcumin: A549, 44.37 µM; H1299, 66.25 µM) using the WST-1 and RTCA assays revealed pronounced inhibition of proliferation in the combination groups, accompanied by decreased cell migration (fold change, untreated cell; 1, CUR-20 µM; 0.681, KAN-20 µM; 0.530, and COMB; 0.0039 for 48 h). The comet assay revealed severe DNA damage (Tail DNA, fold change, untreated cell; 1, CUR-20 µM; 1.2, KAN-20 µM; 3, and COMB; 4.6) in the A549 cells, while MMP analysis (color change from red to green) and apoptotic staining confirmed cell death morphologically (color change from green to orange). Moreover, Western blot analysis demonstrated that the combination markedly enhanced apoptosis in the A549 cells.