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Open AccessArticle

Preclinical Evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse Models of Pancreatic Cancer

1
Department of Gastroenterology and Gastrointestinal Oncology, University Medicine Goettingen, 37075 Goettingen, Germany
2
Department of Physics and Astronomy, University of Waterloo, Waterloo, ON N2L 3G1, Canada
3
Department of Radiotherapy and Radiation Oncology, University Medicine Goettingen, 37075 Goettingen, Germany
*
Author to whom correspondence should be addressed.
Cells 2019, 8(6), 563; https://doi.org/10.3390/cells8060563
Received: 9 May 2019 / Revised: 4 June 2019 / Accepted: 6 June 2019 / Published: 9 June 2019
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)
Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemo- and radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combination with standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-KrasG12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 × 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human and murine pancreatic cancer cell lines in a dose-dependent manner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 µM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KC mice. In the KPC model, 2Br-DAB or gemcitabine monotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DAB was not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation. View Full-Text
Keywords: 1,2-Diamino-4,5-dibromobenzene; femtomedicine compounds; pancreatic cancer; GEMMs; chemoresistance; radiation therapy; radiosensitizer 1,2-Diamino-4,5-dibromobenzene; femtomedicine compounds; pancreatic cancer; GEMMs; chemoresistance; radiation therapy; radiosensitizer
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Goetze, R.G.; Buchholz, S.M.; Ou, N.; Zhang, Q.; Patil, S.; Schirmer, M.; Singh, S.K.; Ellenrieder, V.; Hessmann, E.; Lu, Q.-B.; Neesse, A. Preclinical Evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse Models of Pancreatic Cancer. Cells 2019, 8, 563.

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