Apatinib Mesylate Inhibits the Proliferation and Metastasis of Epithelioid Malignant Peritoneal Mesothelioma In Vitro and In Vivo

Our plain-English summary of Apatinib Mesylate Inhibits the Proliferation and Metastasis of Epithelioid Malignant Peritoneal Mesothelioma In Vitro and In Vivo, by Z.R. Yang, Z.G. Chen, X.M. Du, et al (Frontiers in Oncology, 2020).

The study

• Authors: Z.R. Yang, Z.G. Chen, X.M. Du, Y. Li
• Journal: Frontiers in Oncology
• Published: 2020;10:585079
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objective: Malignant 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.

Methods: We 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.

Results: Our 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%).

Conclusions: We 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.

Copyright © 2020 Yang, Chen, Du and Li.

In plain English

This was a laboratory and animal study of a drug, not a study of asbestos exposure. The authors took tumor tissue from one patient with epithelioid malignant peritoneal mesothelioma. They grew it in nude mice and also grew cells from it in the lab. They then tested apatinib, a drug that blocks a growth-factor receptor called VEGFR-2. In lab dishes, apatinib slowed the growth of the mesothelioma cells more at higher doses and longer times, and it reduced cell movement in two migration tests. It did not produce signs of the type of cell death called apoptosis. Eighteen mice were split into an untreated group, a solvent-only group and an apatinib group, six mice each, for two weeks. Average tumor-spread scores were 9.8, 10.3 and 7.3 respectively. No apatinib-treated mouse had tumor under the diaphragm or in the liver. Body weight was not affected. Small patches of immune cells were seen in the liver and in the heart muscle in 16.7% of the apatinib group. The authors concluded the study suggests therapeutic value for epithelioid mesothelioma. They noted that it used only one tumor model of one cell type and did not measure survival.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (cell culture) and animal experiment using a patient-derived xenograft (PDX) mouse model
• Who was studied: Tumor tissue from one patient with epithelioid malignant peritoneal mesothelioma (Beijing Shijitan Hospital, China), grown as primary cell lines and in nude mice; 22 mice used, of which 18 were randomized into three groups of 6 (blank control, solvent control, apatinib)
• Exposure: The drug apatinib (a VEGFR-2 inhibitor), given to mice by stomach tube for 2 weeks (dose printed as 100 mg/g/day) and added to cultured cells at several concentrations; no asbestos exposure was studied
• Main results:
  • In cultured MPM cells, apatinib inhibited proliferation, with more pronounced effects at higher doses and longer treatment times (P<0.05)
  • After 24 h, the proportion of cells in G2/M phase was 13.82% in controls vs 4.10% with apatinib; the authors interpreted the cell-cycle results as G2/M arrest
  • Wound-healing migration rates were 77.52 ± 2.54% (blank control), 78.50 ± 6.91% (solvent control), 26.43 ± 15.27% (apatinib 25) and 13.03 ± 11.93% (apatinib 50), differences P<0.0001
  • Transwell assay: cells crossing the membrane were 2601.4 ± 289.6 (blank), 2350.4 ± 556.2 (solvent), 1335.8 ± 213.4 (apatinib 25) and 1138.2 ± 385.4 (apatinib 50)
  • Apatinib did not induce apoptosis: no difference in caspase-3 activity between control and apatinib groups (P greater than 0.05)
  • In mice, mean ePCI (tumor spread) scores were 9.8 ± 0.9 (blank control), 10.3 ± 0.9 (solvent control) and 7.3 ± 1.6 (apatinib), P = 0.003 overall
  • Subphrenic and liver tumor invasion were found only in control mice (0/6 in the apatinib group for each)
  • Ki-67 positive rate in tumors was 17.0 ± 8.0% in the apatinib group vs 48.1 ± 11.5% in controls; the VEGFR-2 positive rate difference (61.4 ± 8.7% vs 65.3 ± 9.9%, P = 0.119) was not statistically significant
  • Lymphocyte infiltration, coagulation necrosis and eosinophilic cell fragments were seen in tumor tissue of the apatinib group
  • Apatinib did not affect mouse body weight; focal lymphoid infiltration was found in liver (16.7%) and cardiac muscle (16.7%) of the apatinib group, with no pathologic changes in other important organs
• The authors' conclusion: The authors concluded that, despite its limitations, the study suggests therapeutic value of apatinib for epithelioid mesothelioma, and that further clinical studies are warranted.
• Limitations the authors state:
  • Only one PDX model of mesothelioma was used, of one histological type (epithelioid).
  • Results should not be generalized to other histological types of peritoneal mesothelioma.
  • Survival was not used as an endpoint in the animal study.

Topics

Medical terms in this study, explained in our Lexicon: Metastasis, Epithelioid, Peritoneal Mesothelioma, Apoptosis, Peritoneal Cancer Index (PCI), Necrosis, Eosinophilic.

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