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Radiosensitizing effects of trabectedin on human A549 lung cancer cells and HT-29 colon cancer cells

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Summary

Background and Purpose Trabectedin is a unique alkylating agent with promising effects against a range of solid tumors. In this study, we aimed to examine the cytotoxic and radiosensitizing effects of trabectedin on two human epithelial tumor cell lines in vitro, and its effects on DNA repair capacity. Methods Cancer cells (A549: human lung cancer cells, HT-29: colon cancer cells) were treated with either trabectedin alone for the determination of their growth, or in combination with radiation for the determination of their metabolic activity, proliferation, and clonogenic survival. Besides, the γH2AX foci assay was performed for the assessment of ionizing radiation-induced DNA damage and to evaluate the influence of trabectedin on DNA damage repair. Results Treatment with trabectedin resulted in a growth-inhibiting effect on both cell lines, with the IC50 values remaining within a low nanomolar range. Analyses of metabolic activity confirmed a cytotoxic influence of trabectedin and a BrdU assay demonstrated an antiproliferative effect. When combined with radiation, incubation with trabectedin was found to enhance the radiosensitivity of the tumor cells. The γH2AX foci assay resulted in an increased number of DNA double-strand breaks (DSBs) in cells treated with trabectedin. Conclusion The results of this study underline the antitumor activity of trabectedin at low nanomolar concentrations. We demonstrated that trabectedin enhanced radiation response in human lung (A549) cancer cells and colon (HT-29) cancer cells. Further studies are necessary to examine trabectedin as a potential candidate for future applications in radiotherapy.

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Data availability

The data supporting this study are provided in the results section of this paper. Further datasets used and/or analyzed during the current study are available are stored by the authors at the University Medical Center Rostock.

Abbreviations

BrdU:

Bromodeoxyuridine

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

Dimethylsulfoxide

DSBs:

double strand breaks

FBS:

fetal bovine serum

HR:

homologous recombination

IC50 :

drug concentration causing 50% growth inhibition

ID50 :

radiation dose causing 50% inhibition of surviving fraction

NSCLC:

non-small cell lung carcinoma

SF4:

surviving fractions at 4 Gy

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Funding

The research was performed as part of the employment of the authors by University Medical Center Rostock, Germany.

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Authors and Affiliations

  1. Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, 18059 Rostock, Südring 75, 18059, Rostock, Germany

    Katrin Manda, Tina Präkelt, Tonja Schröder, Stephan Kriesen & Guido Hildebrandt

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  1. Katrin Manda
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  2. Tina Präkelt
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  3. Tonja Schröder
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  4. Stephan Kriesen
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  5. Guido Hildebrandt
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Contributions

K.M. designed the study. T.P. and T.S. performed experiments, as well as acquired and analyzed the data. S.K. developed the radiation setup und performed dosimetry. K.M. and T.P. wrote and drafted the manuscript. G.H. critically revised the manuscript and contributed to materials and tools. All authors read and approved the final manuscript.

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Correspondence to Katrin Manda.

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Manda, K., Präkelt, T., Schröder, T. et al. Radiosensitizing effects of trabectedin on human A549 lung cancer cells and HT-29 colon cancer cells. Invest New Drugs 38, 967–976 (2020). https://doi.org/10.1007/s10637-019-00852-x

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