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

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.

Epithelial/mesenchymal heterogeneity of high‐grade serous ovarian carcinoma samples correlates with miRNA let‐7 levels and predicts tumor growth and metastasis

“…Cells were plated onto a glass slide and exposed to ionizing radiation (protons). Cell irradiation was performed at room temperature using a 250 MeV proton beam as previously described [38]. Samples were exposed to a proton dose of 4 Gy at the center of the spread-out Bragg peak (SOBP) or mock-irradiated.…”

Duocarmycin SA Reduces Proliferation and Increases Apoptosis in Acute Myeloid Leukemia Cells In Vitro

“…seco-DSA is converted to DSA in situ and exhibits identical DNA alkylation efficiency to the natural compound in several cancer cell lines as described by Boger et al [21,22]. More recently, DSA has been shown to increase the sensitivity of glioblastoma multiforme cells to proton irradiation in the sub-nanomolar range in vitro [23]. In this study, we investigated for the first time the efficacy of DSA on AML cells in vitro.…”

“…Since its initial isolation, synthesis and evaluation by the Ichimura and Boger groups, DSA and its congeners have been investigated in several types of solid tumors including small cell lung cancer, uterine cancer, ovarian cancer and glioblastoma multiforme [23,55,56]. However, DSA has not been investigated in blood cancers, or AML specifically.…”

Repurposing approved non-oncology drugs for cancer therapy: a comprehensive review of mechanisms, efficacy, and clinical prospects

“…It attaches to the DNA molecule causing DNA to be alkylated, which causes the cell cycle arrest. It is one of the most successful medications used to treat endometrial, breast, bladder, hepatic, thyroid, and pulmonary malignancies [ 182 ]. Wang et al analyzed 124 patients from January 1996 to July 2018 to analyze the effects of chemotherapeutic treatment with gemcitabine and anthracycline (epirubicin and pirarubicin).…”