Most glioblastoma patients live less than 15 months after diagnosis, even with surgery, radiation and chemotherapy. One reason is the blood-brain barrier, which keeps many drugs out of the brain. A team led by Joseph A. Bauer reports that a modified form of vitamin B12 got through it in animals and collected in tumor tissue.
The compound is nitrosylcobalamin, or NO-Cbl. It is vitamin B12 altered so that it releases nitric oxide. Bauer, the first and corresponding author, works at Nitric Oxide Services, LLC and the Cleveland Clinic Foundation Taussig Cancer Center. The results were published in Oncoscience.
What the team tested
The researchers used three approaches. They screened NO-Cbl against cancer cells in the NCI-60 human tumor cell line panel. They ran pharmacokinetic studies in rats carrying glioblastoma tumors. And they paired it with other treatments in human glioblastoma cell lines.
In the panel, NO-Cbl showed antitumor activity across many cancer types. Cells from central nervous system tumors were moderately sensitive.
The rat work drew the most attention. After systemic dosing, NO-Cbl crossed the blood-brain barrier and built up in glioblastoma tissue. Nitrate levels in tumor tissue stayed high for at least 24 hours, while levels in normal tissue fell faster. The authors read that as a sign the compound lingers in tumors and delivers nitric oxide to them directly.
Working with existing drugs
In U87 and D54 glioblastoma cells, NO-Cbl combined with either TRAIL or temozolomide suppressed growth far more than any single treatment did. Further analysis found synergy across several dose ranges. Temozolomide is a standard chemotherapy for the disease. TRAIL is experimental.
“This pilot study demonstrates that NO-Cbl crosses the BBB, accumulates selectively in brain tumor tissue, and synergizes with established and experimental glioblastoma therapies,” the authors wrote.
Earlier work cited in the paper found that NO-Cbl can trigger cell death through caspase-8 activation, dampen NF-κB survival signaling and strengthen TRAIL receptor signaling through S-nitrosylation. Together, those effects might make tumors more responsive to treatment, including ones that have grown resistant to temozolomide.
Still early
The authors call this a pilot translational study and say more research is needed before anyone considers clinical use. No human data are reported. Next steps they expect include orthotopic validation, refining doses, tracking nitric oxide activity over longer periods, and probing the mechanisms in other central nervous system tumor models.
Bauer’s co-authors on the paper are Annette M. Sysel and Michael J. Dunphy.
Sources
- New vitamin B12 therapy shows promise against deadly brain cancer
- Vitamin B12 compound shows promise against deadly brain cancer
