The Ibr-7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p-EGFR
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Cancer Cell International Open Access
PRIMARY RESEARCH
The Ibr‑7 derivative of ibrutinib radiosensitizes pancreatic cancer cells by downregulating p‑EGFR Biqin Tan1 , Rong Dong1, Bo Zhang2, Youyou Yan2, Qingyu Li1, Fei Wang1 and Nengming Lin1,2*
Abstract Background: Radiotherapy is one of the main treatments for pancreatic cancer, but radiation resistance limits its clinical application. As a result, novel therapeutic agents to improve radiosensitivity are urgently needed. This study aimed to investigate the effect of Ibr-7 (a derivative of ibrutinib) on the radiosensitivity of human pancreatic cancer cells. Methods: The effect of Ibr-7 on pancreatic cancer cell proliferation was detected by CCK-8 assays. Radiosensitivity was assessed by clonogenic formation assays. Cell cycle and cell apoptosis were analysed by flow cytometry. DNA damage was evaluated by immunofluorescence analysis. The expression levels of PARP, Cleaved caspase 3, p-EGFR and EGFR were determined by western blot. Results: Ibr-7 showed an anti-proliferative effect on PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 μmol/L) enhanced the effect of radiation on PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or in combination with radiation. Overexpression of p-EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in the Ibr-7 plus radiation group. Conclusions: Our study indicated the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells. Keywords: Pancreatic cancer, Ibr-7, Radiosensitivity, Apoptosis, EGFR Background Pancreatic cancer is a highly invasive and fatal disease, with a low 5-year survival rate of only 5% [1]. Pancreatic cancer is diagnosed in the middle or terminal stage, and 80% of patients are ineligible for surgery. The treatment options for these patients are chemotherapy and radiation therapy [2, 3]. Gemcitabine is the first-line treatment *Correspondence: [email protected] 1 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, China Full list of author information is available at the end of the article
drug for pancreatic cancer. FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) regimens are available for improving progression-free survival (PFS) and overall survival (OS). Approximately 70% of pancreatic cancer patients receive radiotherapy, either alone or in combination with chemotherapy [4, 5]. However, many patients do not benefit from such cytotoxic drugs alone or together with radiotherapy. Pancreatic cancer cells inevitably develop radioresistance, which is one of the
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