Low-Glucose Conditions of Tumor Microenvironment enhance cytotoxicity of tetrathiomolybdate to neuroblastoma cells
|Článek v odborném periodiku
|Časopis / Zdroj
|Nutrition and Cancer
|Fakulta / Pracoviště MU
|Genetika a molekulární biologie
|tetrathiomolybdate; neuroblastoma; glucose starvation; apoptosis; cancer therapy
|Growth of tumor cells depends on sufficient supply of fermentable substrate, such as glucose. This provokes development of new anti-cancer therapies based on dietary restrictions. However, some tumor cells can lower their glucose dependency and activate processes of ATP formation/saving to retain viability even in limited glucose supply. In addition, tumor cells often loose sensitivity to many conventional anti-cancer drugs in the low-glucose conditions. Thus, development of the drugs effectively killing the tumor cells in nutrient-limited conditions is necessary. In this study, we show an enhanced cytotoxicity of tetrathiomolybdate, the drug exhibiting anti-angiogenic and tumor-suppressing effects, to neuroblastoma SH-SY5Y and SK-N-BE(2) cells in the low-glucose conditions. This preference results from the tetrathiomolybdate-induced upregulation of cell dependency on glucose. The cells treated with tetrathiomolybdate increase the uptake of glucose, production of lactate, activate the Akt- and AMPK signaling pathways and down-regulate COX IV. In cells growing in the low-glucose conditions, these events result in significant decrease of the intracellular ATP supply and apoptosis. We propose TM as suitable agent to be used in combination with dietary restrictions in therapy of neuroblastoma.