A nontoxic N-hydrazinecarbothioamide β-lapachone (BV3) derivative acts as a sensitizer molecule to ionizing radiation on lung cancer cells

Introduction: β-lapachone (β-Lap) and ionizing radiation kill cancer cells synergistically. Herein, we produced three thiosemicarbazone derivatives from β-Lap (BV2, BV3, and BV5) and treated lung cancer cells with BV compounds alone or in combination with gamma radiation; in addition, we assessed the acute toxicity of the compounds in Swiss mice. Methods: The NCI-H292 (lung cancer) cells were irradiated with 1 Gy gamma radiation dose with two protocols: 24 h before treatment with compounds or immediately after treatment with compounds. After radiation, cells were seeded in six-well plates, 24 h late compounds were added to the plate, and incubated for 24 h. After this period, the drug was removed. In another set of experiments, cells were treated with compounds at the half-maximal inhibitory concentration (IC50) concentration during 24 h, then the drug was removed and radiation was applied. Growth was monitored during 11 d. Acute Toxicity of Compounds was evaluated using OECD Guideline 423. Results: Among three compounds tested at the survival clonogenic assay, only BV3 presented a lower IC50 (1.6 μg/mL) when associated with 1 Gy pre-gamma radiation, compared to non-irradiated BV3 treatment (2.8 μg/mL). When cells were first treated (24 h) with β-Lap derivatives at IC50 concentration and then irradiated with 1 Gy, a significant reduction on colony survival was observed for all compounds tested, BV2 (2.1 μg/mL), BV3 (2.8 μg/mL), or BV5 (1.9 μg/mL) resulting in 12%, 11%, 9% colony survival reduction, respectively. Regarding the toxicity, all Swiss mice survived to single pharmacological dose application (2000 mg/kg) of BV compounds. Conclusions: Compound BV3 showed the best radiosensitizing properties among the compounds tested, and no signs of irreversible tissue damage or death were observed when animals were exposed to a single high-dose.