Differential effects of thymoquinone under low-glucose stress in LKB1-null A549 and LKB1-wild-type H1299 lung cancer...

Lung cancer remains one of the leading causes of cancer-related deaths worldwide, and the effects of thymoquinone on lung cancer cells have been increasingly investigated in recent years. Rapidly proliferating cancer cells exhibit increased metabolic activity and energy requirements, and the Liver Kinase B1 (LKB1) plays a crucial role in metabolic adaptation. In this study, the effects of thymoquinone on LKB1-null (A549) and LKB1-wild-type (H1299) lung cancer cell lines were investigated under high and low glucose stress conditions. Under high glucose conditions, thymoquinone showed a dose- and time-dependent cytotoxic effect in H1299 cells, with a 24-hour IC₅₀ value of 23.4 µM. In A549 cells, a hormetic response was observed at low and moderate doses, cytotoxicity occurred only at high doses, and the 24-hour IC₅₀ value was determined as 69.45 µM. Under low glucose conditions, the cytotoxic effect of thymoquinone was increased in both cell lines; 24-hour IC₅₀ values were determined as 15 µM for H1299 and 16 µM for A549 cells. Overall, H1299 cells were found to be more sensitive to thymoquinone, especially at lower doses and earlier time points. Thymoquinone and glucose levels affected autophagy differently depending on the cell line. In H1299 cells, low glucose and thymoquinone administration significantly increased autophagy, while in A549 cells, both low glocose stress and thymoquinone suppressed autophagy. In contrast, thymoquinone increased apoptosis in both cell lines; this increase was particularly pronounced in late-stage apoptosis and was observed at much higher rates in A549 cells. However, LKB1 status alone may not be sufficient to determine the metabolic stress response, and additional molecular factors such as p53 protein may play a role in this process. A possible mechanistic explanation for this observed difference could be that H1299 cells are TP53-null, whereas A549 cells are harbor wild-type TP53. Our findings suggest that the effects of thymoquinone may vary depending on the cellular genetic background and are shaped by multidimensional mechanisms under conditions of metabolic stress, and detailed studies on this subject are needed.

The online version contains supplementary material available at 10.1007/s10616-026-01009-4.