Duocarmycin SA, a potent antitumor antibiotic, sensitizes glioblastoma cells to proton radiation

• Published in: Bioorganic & medicinal chemistry letters 2018-09, Vol.28 (16), p.2688-2692
• Main Authors: Boyle, Kristopher E., Boger, Dale L., Wroe, Andrew, Vazquez, Marcelo
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Duocarmycins; Glioblastoma; Humans; Indoles - pharmacology; Necrosis - chemically induced; Protons; Pyrroles - pharmacology; Radiation-Sensitizing Agents - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.04.008

[Display omitted] •New treatment modalities for glioblastoma multiforme (GBM) are urgently needed.•Duocarmycin SA is an extremely potent cytotoxic agent.•DSA concentrations as low as 0.001 nM sensitized U-138 cells to proton irradiation.•DSA enhance the cytotoxicity of with proton exposures in vitro. New treatment modalities for glioblastoma multiforme (GBM) are urgently needed. Proton therapy is considered one of the most effective forms of radiation therapy for GBM. DNA alkylating agents such as temozolomide (TMZ) are known to increase the radiosensitivity of GBM to photon radiation. TMZ is a fairly impotent agent, while duocarmycin SA (DSA) is an extremely potent cytotoxic agent capable of inducing a sequence-selective alkylation of duplex DNA. Here, the effects of sub-nM concentrations of DSA on the radiosensitivity of a human GBM cell line (U-138) to proton irradiation were examined. Radiation sensitivity was determined by viability, apoptosis, necrosis and clonogenic assays. DSA concentrations as low as 0.001 nM significantly sensitized U-138 cells to proton irradiation. DSA demonstrates synergistic cytotoxicity against GBM cells treated with proton radiation in vitro, which may represent a novel therapeutic alternative for the treatment of GBM.