Induction of ER Stress-Mediated Apoptosis by α-Lipoic Acid in A549 Cell Lines

Abstract

Backgroundα-Lipoic acid (α-LA) has been studied as an anticancer agent as well as a therapeutic agent for diabetes and obesity. We performed this study to evaluate the anticancer effects and mechanisms of α-LA in a lung cancer cell line, A549.Materials and Methodsα-LA-induced apoptosis of A549 cells was detected by fluorescence-activated cell sorting analysis and a DNA fragmentation assay. Expression of apoptosis-related genes was analyzed by western blot and reverse transcription-polymerase chain reaction analyses.Resultsα-LA induced apoptosis and DNA fragmentation in A549 cells in a dose- and time-dependent manner. α-LA increased caspase activity and the degradation of poly (ADP-ribose) polymerase. It induced expression of endoplasmic reticulum (ER) stress-related genes, such as glucose-regulated protein 78, C/EBP-homologous protein, and the short form of X-box binding protein-1, and decreased expression of the anti-apoptotic protein, X-linked inhibitor of apoptosis protein. Reactive oxygen species (ROS) production was induced by α-LA, and the antioxidant N-acetyl-L-cysteine decreased the α-LA-induced increase in expression of apoptosis and ER stress-related proteins.Conclusionα-LA induced ER stress-mediated apoptosis in A549 cells via ROS. α-LA may therefore be clinically useful for treating lung cancer.

Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo

“…This result is in agreement with similar findings by other groups concerning induction of apoptosis. 17,24,[26][27][28][29][30][31] In addition to the in vitro experiments, studies with LPA were performed in a mouse model after inoculation of SkBr3 tumor cells. LPA was clearly able to reduce the tumor volume and T/M ratios compared with untreated controls.…”

Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential

“…Oxidative stress possesses also a main role in tumorigenesis [12]. LA has been administered as an anticancer agent mainly in experimental studies of different tumorigenesis cells type with encouraging results [2,16,23,33,41,43]. Until now the molecular mechanisms implicated in this process are still unknown.…”

“…Another possible hypothesis could be linked to the cancer cells metabolism, which converts and transforms preferentially the glucose to lactate, a mechanism known as the Warburg effect [33]. In fact, LA is the cofactor of pyruvate dehydrogenase which converts and transforms the pyruvate molecules to acetyl CoA, resulting in a decrement in the formation of lactate molecules [16].…”

Obovatol Induces Apoptosis in Non‐small Cell Lung Cancer Cells via C/EBP Homologous Protein Activation

“…There are accumulating evidences that the induction of endoplasmic reticulum (ER) stress proteins is involved in apoptosis in lung cancer(Lin et al, ; Moriya et al, ; Zhao et al, ; Kim et al, ). Among ER stress proteins, three ER transmembrane proteins such as inositol‐requiring enzyme‐1 (IRE1), activating transcription factor 6 and PKR‐like ER kinase respond to the accumulation of unfolded proteins as survival response (Fels and Koumenis, ).…”