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Mafosfamide, a cyclophosphamide analog, causes a proinflammatory response and increased permeability on endothelial cells in vitro

Bone Marrow Transplantation volume 58, pages 407–413 (2023)Cite this article

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Abstract

Post-transplantation cyclophosphamide (PTCy) has decreased GVHD incidence. Endothelial damage in allo-HCT is caused by multiple factors, including conditioning treatments and some immunosupressants, and underlies HCT-complications as GVHD. Nevertheless, the specific impact of PTCy on the endothelium remains unclear. We evaluated the effect of mafosfamide (MAF), an active Cy analog, on endothelial cells (ECs) vs. cyclosporine A (CSA), with known damaging endothelial effect. ECs were exposed to MAF and CSA to explore changes in endothelial damage markers: (i) surface VCAM-1, (ii) leukocyte adhesion on ECs, (iii) VE-cadherin expression, (iv) production of VWF, and (v) activation of intracellular signaling proteins (p38MAPK, Akt). Results obtained (expressed in folds vs. controls) indicate that both compounds increased VCAM-1 expression (3.1 ± 0.3 and 2.8 ± 0.6, respectively, p < 0.01), with higher leukocyte adhesion (5.5 ± 0.6, p < 0.05, and 2.8 ± 0.4, respectively). VE-cadherin decreased with MAF (0.8 ± 0.1, p < 0.01), whereas no effect was observed with CSA. Production of VWF augmented with CSA (1.4 ± 0.1, p < 0.01), but diminished with MAF (0.9 ± 0.1, p < 0.05). p38MAPK activation occurred with both compounds, being more intense and faster with CSA. Both drugs activated Akt, with superior MAF effect at longer exposure. Therefore, the cyclophosphamide analog MAF is not exempt from a proinflammatory effect on the endothelium, though without modifying the subendothelial characteristics.

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Fig. 1: Expression of VCAM-1 on ECs exposed to mafosfamide or cyclosporine A, separately.
Fig. 2: Expression of VE-cadherin on ECs exposed to mafosfamide or cyclosporine A, separately.
Fig. 3: Expression of VWF on ECs exposed to mafosfamide or cyclosporine A, separately.
Fig. 4: Differential activation of the intracellular signaling proteins p38MAPK and Akt in ECs exposed to mafosfamide or cyclosporine A, separately.

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The authors affirm that software application or custom code is not applicable in this study.

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Acknowledgements

We thank the Primary Hemostasis laboratory staff (Hospital Clínic, Barcelona) for technical support.

Funding

Study partially supported by Instituto de Salud Carlos III (FIS PI19/00888), Fundació Marató de TV3 (202026–10), Deutsche José Carreras Leukämie-Stiftung (03 R/ 2019), Generalitat de Catalunya (2017-SGR675, CERCA), Contrato Clínico de investigación “Emili Letang - Josep Font”.

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Authors and Affiliations

  1. Josep Carreras Leukaemia Research Institute (Campus Clínic), Barcelona, Spain

    Julia Martinez-Sanchez, Marta Palomo & Enric Carreras

  2. Hemostasis and Erythropathology Laboratory, Hematopathology, Department of Pathology, Centre de Diagnòstic Biomèdic (CDB), Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain

    Julia Martinez-Sanchez, Roger Pascual-Diaz, Marta Palomo, Ana Belén Moreno-Castaño, Gines Escolar & Maribel Diaz-Ricart

  3. Barcelona Endothelium Team, Barcelona, Spain

    Julia Martinez-Sanchez, Marta Palomo, Ana Belén Moreno-Castaño, Gines Escolar, Enric Carreras & Maribel Diaz-Ricart

  4. Medical Intensive Care Unit, Department of Internal Medicine, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain

    Helena Ventosa

  5. Hematology Department, Bone Marrow Transplantation Unit, Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Barcelona, Spain

    María Queralt Salas & Montserrat Rovira

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Contributions

JMS and MDR designed the study and wrote the manuscript; JMS and RPD were responsible for the experimental work and the statistical analysis of results; JMS, MP, MDR and GE designed the figures; MP, ABMC, HV, MQS, MR, GE and EC contributed to discuss the results; all the authors contributed to the review and editing of the final manuscript.

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Correspondence to Maribel Diaz-Ricart.

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None of the authors have conflicts of interest directly related to this work. MDR and EC have received honoraria from Jazz Pharmaceuticals.

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Martinez-Sanchez, J., Pascual-Diaz, R., Palomo, M. et al. Mafosfamide, a cyclophosphamide analog, causes a proinflammatory response and increased permeability on endothelial cells in vitro. Bone Marrow Transplant 58, 407–413 (2023). https://doi.org/10.1038/s41409-023-01912-w

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