α‐Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells

Abstract

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

The effects of lipoic acid on respiratory diseases

“…LA (91 mg/kg i.p. three times per week for two weeks) significantly enhanced lung cancer cell apoptosis in mice by suppressing the PDK1/NRF2 axis and increasing ROS levels [97] . In another study, researchers fed mice 50 mg/kg/day for 18 days, and LA administration markedly decreased lung cancer proliferation by activating mTOR-mediated autophagy inhibition [14] .…”

“…In vitro , treatment with 0.5–2 mM LA significantly inhibited the proliferation of human non-small cell lung cancer (NSCLC) cells, including PC-9, HCC827, A549 and H1975 cells [14] , [94] , [95] . In 549 and PC-9 cells, treatment with 0.5–1.5 mM LA promoted apoptosis [96] , [97] , [98] . Cancer stem cells (CSCs) are not only a regenerative source of cancer cells but also a critical factor in tumour metastasis and recurrence [99] .…”

Novel oxaliplatin(iv) complexes conjugated with ligands bearing pendant 1,2-dithiolane/1,2-diselenolane/cyclopentyl motifs

“…Intriguingly, the four cyclopentyl-containing Pt(IV) analogues (9)(10)(11)(12), which were synthesized for checking to which extent cytotoxicity was specifically conferred by sulfur/selenium in the axial ligands or just by the presence of a rather lipophilic moiety, turned out to be more cytotoxic than sulfur/ selenium species. Di-functionalized species showed a higher cytotoxic activity than mono-functionalized species in all cell lines and complexes 10-12 proved to be comparable or even more effective than their parent compound oxaliplatin.…”

“…9, 62.4, 40.1, 36.6, 36.1, 32.9, 28.6, 26.0, 25.3, 24.1 ppm. oxaPt(CpA)(PhB) [11]. Starting from complex 9 (66 mg, 0.114 mmol) and PhB anhydride (141 mg, 0.455 mmol), complex 11 was prepared using the same procedure as for complex 3.…”

“…9 Those biological functions have endowed ALA with therapeutic potentials in diseases associated with ROS production, including cancer. 10 a , b For example, it has been demonstrated that administration of ALA can promote apoptosis in non-small cell lung cancer by inhibiting PDK, resulting in enhanced mitochondrial ROS/apoptosis pathway, 11 and treatment of hepatoma cells with ALA increases ROS production, which triggers p53-dependent apoptosis. 12 In addition, ALA, as an effective neuro-protective agent, is able to prevent or minimize oxaliplatin-induced neurotoxicity, without adverse effects.…”