Alpha-lipoic acid (LA), which plays a pivotal role in mitochondrial energy metabolism, is an endogenous
dithiol compound with an array of antioxidative functions. It has been shown that LA triggers cell death in tumor cell lines, whereas non-transformed cells are hardly affected. In the present study, we analyzed the cytotoxicity of LA on
colorectal cancer (CRC) cells differing in their p53 status and investigated a putative synergistic effect with the anticancer
drug 5-fluorouracil (5-FU). We show that LA induces a dose-dependent decrease in cell viability, which was independent of the p53 status as attested in isogenic p53-proficient and p53-deficient cell lines. This effect was largely attributable to cell death induction as revealed by
Annexin-V/PI staining. LA-treated HCT116 cells underwent
caspase-dependent and
caspase-independent cell death, which was blocked by the pan-
caspase inhibitor zVAD and the RIP-
kinase inhibitor
Necrostatin-1, respectively. In CaCO-2 and HT29 cells, LA induced
caspase-dependent cell demise via activation of
caspase-9,
caspase-3 and
caspase-7 with subsequent PARP-1 cleavage as demonstrated by immunoblot analysis, activity assays and pan-
caspase inhibition. Interestingly, LA treatment did neither activate p53 nor induced genotoxic effects as shown by lack of
DNA strand breaks and phosphorylation of
histone 2AX. Finally, we provide evidence that LA increases the cytotoxic effect induced by the anticancer
drug 5-FU as revealed by significantly enhanced cell death rates in HCT116 and CaCO-2 cells. Collectively, these findings demonstrate that LA induces CRC cell death independent of their p53 status and potentiates the cytotoxicity of
5-FU without causing DNA damage on its own, which makes it a candidate for
tumor therapy.