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

• Main Authors: Robert G. Goetze, Soeren M. Buchholz, Ning Ou, Qinrong Zhang, Shilpa Patil, Markus Schirmer, Shiv K. Singh, Volker Ellenrieder, Elisabeth Hessmann, Qing-Bin Lu, Albrecht Neesse
• Format: Article
• Language: English
• Published: MDPI AG 2019-06-01
• Series: Cells
• Subjects: 1,2-Diamino-4,5-dibromobenzene; femtomedicine compounds; pancreatic cancer; GEMMs; chemoresistance; radiation therapy; radiosensitizer
• Online Access: https://www.mdpi.com/2073-4409/8/6/563

<b>Background:</b> 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. <b>Methods:</b> Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine <i>LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre</i> (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in <i>LSL-Kras^G12D/+;p48-Cre</i> (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 &#215; 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. <b>Results:</b> 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 &#181;M 2Br-DAB + radiation treatment compared with vehicle control (<i>p</i> = 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. <b>Conclusions:</b> 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.