The role of GAPDH in the selective toxicity of CNP in melanoma cells.

BACKGROUND: Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells. In conclusion, the redox-active CNP exhibited both prooxidative as well as antioxidative properties. In that context, CNP induced mitochondrial dysfunction in the studied melanoma cells via generation of reactive oxygene species (primarily hydrogen peroxide (H2O2)), but that does not account for 100% of the toxicity. AIM: Cancer cells often show an increased glycolytic rate (Warburg effect), therefore we focused on CNP mediated changes of the glucose metabolism. RESULTS: It has been shown before that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity is regulated via oxidation of a cysteine in the active center of the enzyme with a subsequent loss of activity. Upon CNP treatment, formation of cellular lactate and GAPDH activity were significantly lowered. The treatment of melanoma cells and melanocytes with the GAPDH inhibitor heptelidic acid (HA) decreased viability to a much higher extent in the cancer cells than in the studied normal (healthy) cells, highlighting and supporting the important role of GAPDH in cancer cells. CONCLUSION: We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a target protein for CNP mediated thiol oxidation.

The natural chalcone cardamonin selectively induces apoptosis in human neuroblastoma cells.

Neuroblastoma is the most common extracranial malignant tumor in childhood. Approximately 60% of all patients are classified as high-risk and require intensive treatment including non-selective chemotherapeutic agents leading to severe side effects. Recently, phytochemicals like the natural chalcone cardamonin (CD) have gained attention in cancer research. For the first time, we investigated the selective anti-cancer effects of CD in SH-SY5Y human neuroblastoma cells compared to healthy (normal) fibroblasts (NHDF). Our study revealed selective and dose-dependent cytotoxicity of CD in SH-SY5Y. The natural chalcone CD specifically altered the mitochondrial membrane potential (ΔΨm), as an early marker of apoptosis, in human neuroblastoma cells. Caspase activity was also selectively induced and the amount of cleaved caspase substrates such as PARP was thus increased in human neuroblastoma cells. CD-mediated apoptotic cell death was rescued by pan caspase inhibitor Z-VAD-FMK. The natural chalcone CD selectively induced apoptosis, the programmed cell death, in SH-SY5Y human neuroblastoma cells whereas NHDF being a model for normal (healthy) cells were unaffected. Our data indicates a clinical potential of CD in the more selective and less harmful treatment of neuroblastoma.