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. 2018 Sep 1;28(16):2688-2692.
doi: 10.1016/j.bmcl.2018.04.008. Epub 2018 Apr 4.

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

Kristopher E Boyle  1 , Dale L Boger  2 , Andrew Wroe  3 , Marcelo Vazquez  4
Affiliations

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

Kristopher E Boyle et al. Bioorg Med Chem Lett. .

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Duocarmycin SA (DSA).
Fig. 2.
Fig. 2.
Sensitivity of U-138 cells to DSA, proton irradiation and TMZ at 72 h. post-treatment. (A) Number of viable cells exposed to DSA, (B) proton irradiation and (C) TMZ. (*p < 0.05, **p < 0.01, ***p < 0.001).
Fig. 3.
Fig. 3.
U-138 cell viability after proton irradiation alone, DSA alone or combined DSA and proton at 72 h. post treatment.
Fig. 4.
Fig. 4.
Incidence of apoptosis (A) or necrosis (B) in U-138 cell at 72 h after treatment with protons alone or combined with DSA.
Fig. 5.
Fig. 5.
Cell survival curves for U-138 cells treated with DSA (panel A), protons (panel B) and protons and 0.001 nM DSA (panel C).
See this image and copyright information in PMC

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