Authors:

Irene Lazanyi

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About Paper:

Breast cancer brain metastasis (BCBM) is a lethal disease sequela that develops in up to 40% of breast cancer patients and is associated with a poor prognosis [1]. Therapeutic options remain limited because most systemic agents cannot cross the blood-brain barrier (BBB) [2]. Consequently, whole-brain radiation therapy (WBRT) remains the standard of care, despite its suboptimal outcomes and severe cognitive side effects [2]. Identifying radiosensitizing agents, which enhance the efficacy of WBRT, could improve clinical outcomes in patients with BCBM. This study investigates Triapine (3AP), an inhibitor of the RRM2 subunit of ribonucleotide reductase, as a potential radiosensitizer. RRM2 is a key enzyme in DNA repair and is associated with tumor resistance to DNA-damaging agents. Since radiation therapy (RT) induces double-stranded DNA breaks, inhibiting RRM2 may enhance radiation-induced cytotoxicity. BCBM cell line, MDA-MB-231-BR, was cultured and treated with control (Dimethyl sulfoxide (DMSO)), RT, 3AP, and a combination of 3AP and RT. Western blots displayed that y-H2AX, a marker of DNA damage, increased in the combination subgroup compared to radiation. Colony formation and cell viability assays displayed decreased (BCBM) cell survival in the combination subgroup. Immunocytochemistry to assess DNA damage through y-H2AxX foci visualization showed an increase in the number of foci in the combination group in comparison to radiation alone. /n vivo experiments were conducted where mice with intracranially implanted 231-BR tumors were treated with DMSO, 3AP, Radiation or a combination of Radiation and 3AP. Significant reduction in tumor volume and increase in survival were observed in the combination group in comparison to the radiation-only group. Preliminary results suggest that 3AP enhances RT-induced DNA damage by inhibiting RRM2, reducing BCBM cell survival. This approach offers a promising strategy to overcome therapeutic resistance in BCBM and may serve as a foundation for future clinical investigation of 3AP as a radiosensitizer.

Source:

Northwestern University

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Co-authors:

Irene Lazanyi