Induction of Apoptosis in neoplastic cells by depletion of vitamin B12

Abstract

Methionine synthase, a critical enzyme in deoxyribonucleotide biosynthesis for DNA replication, requires vitamin B 12 as a cofactor. We have tested the hypothesis that depletion of cells of vitamin B 12 would block growth of neoplastic cells and divert them into apoptosis and could form the basis of a new therapeutic strategy for cancer treatment. Using nitrous oxide to inactivate vitamin B 12 we show that, in a variety of cell lines in vitro, methionine synthase is rapidly inhibited, the cells cease proliferation and undergo apoptosis. The kinetics of cell death, once started, are similar to those observed following methotrexate treatment or serum withdrawal. This is the first observation of apoptosis being induced following depletion of an essential metabolite as opposed to the more conventional strategy of adding a toxic drug to damage cells thereby triggering apoptosis. Moreover, vitamin B 12 depletion has no effect on the nonproliferating cell population.

Cobalamin and normal prions: A new horizon for cobalamin neurotrophism

“…No histological signs of apoptosis were observed in any SC region of Cbl-D rats, despite reports of apoptosis have been reported by others in the CNS of TNF-a-treated rats [24,25], in cultured Cbl-deprived neoplastic cells [26], and, more recently, in cultured neuroblastoma cells transfected with plasmid containing transcobalamin-oleosin, a very efficient chelator of Cbl [27].…”

Characterization of the promoter region of TCblR/CD320 gene, the receptor for cellular uptake of transcobalamin-bound cobalamin

“…The regulation and over expression of TCblR in various cancers is of particular interest in light of Cbl requirement for folate recycling and DNA synthesis. Down regulation of TCblR or blocking Cbl uptake in cancer cells are strategies likely to arrest proliferation of cancer cells (McLean et al, 1997; Walker et al, 1997). Identifying cancers with sustained high levels of TCblR expression, would also permit delivery of drugs and toxins preferentially to these tumors.…”

Establishment of an apoptosis-resistant and growth-controllable cell line by transfecting with inducible antisense c-Jun gene

“…The addition of a minor amount of concentrated fresh medium after this growth blocking would further improve survival of the cells. However, blocking growth of neoplastic cells itself usually diverts them into apoptosis, suicidal cell death (Walker et al, 1997). For example, the intensive growth inhibition of hybridoma cells by excess thymidine was accompanied by cell death (Suzuki and Ollis, 1990).…”