Abstract
BackgroundBrain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected. Standard of care remains ineffective in both types of cancer with the challenge of overcoming the blood brain barrier (BBB) exacerbating the clinical problem. Our purpose is to determine and characterize the potential of albendazole (ABZ) as a cytotoxic and radiosensitizing agent against MM and SCLC cells.MethodsHere, ABZ's mechanism of action as a DNA damaging and microtubule disrupting agent is assessed through analysis of histone H2AX phosphorylation and cell cyle progression. The cytotoxicity of ABZ alone and in combination with radiation therapy is determined though clonogenic cell survival assays in a panel of MM and SCLC cell lines. We further establish ABZ's ability to act synergistically as a radio-sensitizer through combination index calculations and apoptotic measurements of poly (ADP-ribose) polymerase (PARP) cleavage.ResultsABZ induces DNA damage as measured by increased H2AX phosphorylation. ABZ inhibits the growth of MM and SCLC at clinically achievable plasma concentrations. At these concentrations, ABZ arrests MM and SCLC cells in the G2/M phase of the cell cycle after 12 hours of treatment. Exploiting the notion that cells in the G2/M phase are the most sensitive to radiation therapy, we show that treatment of MM and SCLC cells treated with ABZ renders them more sensitive to radiation in a synergistic fashion. Additionally, MM and SCLC cells co-treated with ABZ and radiation exhibit increased apoptosis at 72 hours.ConclusionsOur study suggests that the orally available antihelminthic ABZ acts as a potent radiosensitizer in MM and SCLC cell lines. Further evaluation of ABZ in combination with radiation as a potential treatment for MM and SCLC brain metastases is warranted.
Highlights
Melanoma and small cell lung cancer (SCLC) have a high propensity for metastasizing to the brain, accounting for the most common and third most common cause of brain metastasis, respectively [1]
With no currently FDA-approved agents that cross the blood brain barrier (BBB) to target SCLC, conventional therapy for brain metastasis is limited to whole brain radiation therapy
Albendazole treatment causes phosphorylation of H2AX From a screen of 2000 compounds, we identified 4 BZs that were selectively cytotoxic to melanoma cells as compared to normal melanocytes [5]
Summary
Melanoma and small cell lung cancer (SCLC) have a high propensity for metastasizing to the brain, accounting for the most common and third most common cause of brain metastasis, respectively [1]. With no currently FDA-approved agents that cross the blood brain barrier (BBB) to target SCLC, conventional therapy for brain metastasis is limited to whole brain radiation therapy. Albendazole (ABZ) is another marketed antihelminthic that is structurally related to MBZ. ABZ, has the unique advantage of crossing the BBB, a characteristic that is used to treat parasitic infections of the central nervous system and may be harnessed to potentially target brain metastasis [6]. Brain metastases afflict approximately half of patients with metastatic melanoma (MM) and small cell lung cancer (SCLC) and represent the direct cause of death in 60 to 70% of those affected. Our purpose is to determine and characterize the potential of albendazole (ABZ) as a cytotoxic and radiosensitizing agent against MM and SCLC cells
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