Abstract
ObjectiveMalignant peritoneal mesothelioma (MPM) is a rare malignancy with few effective molecular therapies. In this study, we evaluated the anti-tumor activity and safety of apatinib, a vascular endothelial growth factor receptor 2 inhibitor, in MPM in vitro and in vivo.MethodsWe established several patient-derived xenograft (PDX) models and primary cell lines of MPM. The cell lines were used to study the effects of apatinib on proliferation, cell cycle, migration, and apoptosis by CCK8, flow cytometry, wound-healing, Transwell, DAPI staining, and caspase-3 assays, respectively. For in vivo study, apatinib was delivered by gastric gavage into PDX models, and then efficacy and toxicity were determined by experimental peritoneal cancer index (ePCI) score and pathological examinations.ResultsOur results showed that apatinib significantly inhibited the proliferation and migration of MPM cells in vitro and induced cell cycle arrest. Studies on PDX models concurred that apatinib effectively suppressed subphrenic and liver invasions of nude mice. Moreover, histopathological analysis found that lymphocyte infiltration, coagulation necrosis and eosinophilic cell fragments were detected in tumor tissues after apatinib treatment. Apatinib showed no obvious effects on body mass of models and did not affect function of important organs, except for occasional focal lymphoid infiltration of liver (16.7%) and cardiac muscle (16.7%).ConclusionsWe successfully established MPM PDX models and primary cell lines, and confirmed that apatinib effectively inhibited proliferation and metastasis of MPM in vitro and in vivo study.
Highlights
Malignant peritoneal mesothelioma (MPM) is a rare malignancy characterized by highly aggressive behavior and poor prognosis
Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article
Apatinib was dissolved in 100% dimethyl sulfoxide (DMSO; Sigma, USA) to yield a 151 mM stock solution, which was diluted to the specified concentration in subsequent experiment by using Dulbecco’s Modified Eagle’s Medium (DMEM; Thermo Fisher Scientific, USA)
Summary
Malignant peritoneal mesothelioma (MPM) is a rare malignancy characterized by highly aggressive behavior and poor prognosis. MPM accounts for 10%–30% of all malignant mesothelioma, and the median survival time of patient limited 5 to 12 months [1, 2]. There is no effective targeted therapeutic approaches to MPM, and the Peritoneal Surface Oncology Group International (PSOGI) recommends the combination of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as the standard treatment [3, 4]. The median survival of treated patients can be extended to 3 years, but some patients still showed no benefits from CRS + HIPEC [5,6,7]. Apatinib has showed antitumor effects on other kinds of tumors, such as sarcoma, breast cancer, ovarian cancer, and acute lymphoblastic leukemia (ALL) [10,11,12,13,14]. Its expected inhibitory effect on MPM remains to be elucidated
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