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

Cells

Shilpa Patil¹  Albrecht Neesse¹  Elisabeth Hessmann¹  ShivK. Singh¹  RobertG. Goetze¹  Volker Ellenrieder¹  SoerenM. Buchholz¹  Ning Ou²  Qing-Bin Lu²  Qinrong Zhang²  Markus Schirmer³ 

[1] Department of Gastroenterology and Gastrointestinal Oncology, University Medicine Goettingen, 37075 Goettingen, Germany;Department of Physics and Astronomy, University of Waterloo, Waterloo, ON N2L 3G1, Canada;Department of Radiotherapy and Radiation Oncology, University Medicine Goettingen, 37075 Goettingen, Germany;

关键词: 1,2-Diamino-4,5-dibromobenzene;    femtomedicine compounds;    pancreatic cancer;    GEMMs;    chemoresistance;    radiation therapy;    radiosensitizer;   

DOI  :  10.3390/cells8060563

来源: DOAJ

【 摘 要 】

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-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-Kras^G12D/+;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.

【 授权许可】

Unknown