Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasi
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PRECLINICAL STUDIES
Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasing DNA damage in pancreatic cancer cell lines Yuqian Liu 1 & Ruochen Zang 1 & Feifei Li 1 & Chuanqin Shi 1 & Jianchun Zhao 1,2 & Lili Zhong 1 & Xin Wang 1,2,3 & Jinbo Yang 1,2,3 & Wenbao Li 1,2,3 Received: 10 August 2019 / Accepted: 22 October 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Summary Pancreatic cancer (PC) is a highly malignant cancer with poor prognosis. Although gemcitabine (GEM; 2′,2′-difluorodeoxycytidine) has been used as the first-line chemotherapeutic agent in PC treatment for decades, its limited efficacy remains a significant clinical issue, which may be resolved by GEM combination therapy. In this study, we aimed to investigate the antitumor effects of MBRI-001 in combination with GEM in BxPC-3 and MIA PaCa-2 human PC cell lines. In vitro and in vivo results indicate that MBRI-001 showed synergistic activity with GEM. GEM induced apoptosis by increasing DNA damage (phosphorylated core histone protein H2AX (γ-H2AX)), MBRI-001 activated mitochondrial-apoptotic pathway (cleaved polyADP ribose polymerase (PARP)). Thus, the combination of the two intensified both apoptosis and DNA damage and showed significantly superior anti-tumor activity compared to each agent alone. The adoption of combination of MBRI-001 with GEM may be beneficial as they act synergistically and thus, can be a potential therapeutic choice for improving the prognosis of PC patients in the future. Keywords Pancreatic cancer . MBRI-001 . Gemcitabine . DNA damage . Apoptosis
Introduction Pancreatic cancer (PC) is one of the most lethal and least curable human malignancies. In 2018, PC emerged as the seventh leading cause of cancer-related deaths worldwide and the sixth leading in China [1, 2]. The poor prognosis of PC can be attributed to its high metastatic potential, significant chemoresistance, atypical symptoms, and limited treatment * Jinbo Yang [email protected] * Wenbao Li [email protected] 1
School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
2
Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China
3
Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China
options in clinical settings [3, 4]. The five-year survival rate of PC is 1 indicates synergistic, additive, or antagonistic effect, respectively. The CI was calculated using CompuSyn version 1.0.
Immunofluorescence assay The expression of β-tubulin and γ-H2AX were evaluated by Immunofluorescence with antibody β-tubulin (1:100) or γH2AX (1:100), the procedures were described previously [20].
Western blotting Western blot was performed as previously described [20] with antibody PARP (1:2000), γ-H2AX (1:1000) or GAPDH (1:3000). Densities of the western blotting bands were quantified using ImageJ 19.0. Fig. 2 Plinabulin and MBRI-001 inhibited cell proliferation a
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