Abstract
Simple SummaryThe most important biological function of vitamin B12 (cobalamin) is to accomplish DNA synthesis, which is necessary for cell division. Cobalamin deficiency may be especially acute for rapidly dividing cells, such as glioblastoma cells. Therefore, cobalamin antagonists offer a medicinal potential for developing anti-glioma agents. In the present study, we revealed, for the first time, that the induction of cobalamin deficiency by vitamin B12 antagonist with affinity to key transporter of cobalamins, inhibited glioblastoma cells growth and promoted cell cycle arrest. The effect was observed for non-toxic concentration of the agent, as demonstrated on zebrafish. Moreover, as compared to our previous study, the cytostatic effect of the agent was more pronounced in glioblastoma cells than in normal astrocytes. We believe that the study may become the basis for further in vitro and in vivo experiments concerning cobalamin deprivation as a potential therapeutic strategy for glioblastoma.The most important biological function of vitamin B12 is to accomplish DNA synthesis, which is necessary for cell division. Cobalamin deficiency may be especially acute for rapidly dividing cells, such as glioblastoma cells. Therefore, cobalamin antagonists offer a medicinal potential for developing anti-glioma agents. In the present study, we developed an in vitro model of cobalamin deficiency in glioblastoma cells. Long-term treatment of cells with the cobalamin analogue, hydroxycobalamin [c-lactam] (HCCL) was applied to induce an increase of hypocobalaminemia biomarker. Cytometric assays demonstrated that vitamin B12 promoted glioblastoma cells proliferation, whereas the treatment of cells with HCCL caused a dramatic inhibition of cell proliferation and an induction of cell cycle arrest at the G2/M phase. Vitamin B12 counteracted all the observed effects of HCCL. In the in silico study, we characterized the molecular interactions between HCCL and transcobalamin II (TCII). We have demonstrated that HCCL shares similar interactions with TCII as naturally occurring cobalamins and therefore may act as a competitive inhibitor of this key transporter protein. We assessed the impact of HCCL on the mortality or developmental malformations of zebrafish embryos. Collectively, our findings suggest that the use of cobalamin transport antagonists as potential anti-glioma agents would be worth exploring further.
Highlights
Glioblastoma (GB) is one of the deadliest neoplasms, showing a five-year survival rate of 4–5%
The culture of U-87 MG glioblastoma cells was examined after exposure to hydroxycobalamin [c-lactam] (HCCL) (20 or 50 μg/mL), B12 (50 μg/mL) or HCCL (50 μg/mL) in combination with B12 (50 μg/mL)
After nine days of the experiment, the number of cells in the culture exposed to 20 μg/mL or 50 μg/mL HCCL was reduced by approximately 30%
Summary
Glioblastoma (GB) is one of the deadliest neoplasms, showing a five-year survival rate of 4–5%. The mean survival of patients with GB remains below 20 months despite numerous advances in medical research [1,2,3]. Several factors may limit the effectiveness of current treatments for GB, including molecular heterogeneity, tumor cell invasion, and the multidrug resistance proteins of the blood-brain barrier, which prevents the accumulation of xenobiotics within the central nervous system [4]. During the development of new anticancer agents, particular attention should be paid to the differences between normal and cancer cells, as potential targets. One of the characteristics of cancer cells is the high demand for cobalamin (Cbl) known as vitamin B12 (B12) [5,6]. Two proteins involved in the cellular uptake of cobalamin: transcobalamin II (TCII) and transcobalamin
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