Embryo‐derived teratoma biological system reveals antitumor and embryotoxic activity of valproate

Scientific paper - Original scientific paper

• Author: Milvija Plazibat
• Author: Ana Katušić Bojanac
• Author: Marta Himerleich Perić
• Author: Ozren Gamulin
• Author: Mario Rašić
• Author: Vedran Radonić
• Author: Marko Škrabić
• Author: Maria Krajačić
• Author: Jure Krasić
• Author: Nino Sinčić
• Author: Gordana Jurić‐Lekić
• Author: Maja Balarin
• Author: Floriana Bulić‐Jakuš
• Author's institution: University of Zagreb; School of Medicine; (Department of Histology and Embryology)
• Author's institution: University of Zagreb; School of Medicine; (Department of Internal Medicine)
• Author's institution: University of Zagreb; School of Medicine; (Department of Surgery)
• Author's institution: University of Zagreb; School of Medicine; (Department of Medical Biology)
• Author's institution: University of Zagreb; School of Medicine; (Department of Physics and Biophysics)
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Cytology, Histology and Embryology
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Surgery
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine

Abstract (english)

Antiepileptic/teratogen valproate (VPA) is a histone deacetylase inhibitor/epigenetic drug proposed for the antitumor therapy where it is generally crucial to target poorly or undifferentiated cells to prevent a recurrence. Transplanted rodent gastrulating embryos-proper (primitive streak and three germ layers) are the source of teratoma/teratocarcinoma tumors. Human primitive-streak remnants develop sacrococcygeal teratomas that may recur even when benign (well differentiated). To screen for unknown VPA impact on teratoma-type tumors, we used original 2-week embryo-derived teratoma in vitro biological system completed by a spent media metabolome analysis. Gastrulating 9.5-day-old rat embryos-proper were cultivated in Eagle's minimal essential medium (MEM) with 50% rat serum (controls) or with the addition of 2 mmVPA. Spent media metabolomes were analyzed by FTIR. Compared to controls, VPA acetylated histones; significantly diminished overall teratoma growth, impaired survival, increased the apoptotic index, and decreased proliferation index and incidence of differentiated tissues (e.g., neural tissue). Control teratomas continued to grow and differentiate for 14 days in isotransplants in vivo, but in vitro VPA-treated teratomas resorbed. Principal component analysis of FTIR results showed that spent media metabolomes formed well-separated clusters reflecting the treatment and day of cultivation. In metabolomes of VPA-treated teratomas, we found elevation of previously described histone acetylation biomarkers [amide I α-helix and A(CH3 )/A(CH2 )]) with apoptotic biomarkers within the amide I region for β-sheets, and unordered and CH2 vibrations of lipids. VPA may be proposed for therapy of the undifferentiated component of teratoma tumors and this biological system completed by metabolome analysis, for a faster dual screening of antitumor/embryotoxic agents.

• Keywords (english): IR spectroscopy; histone deacetylase inhibitor; teratoma; valproate
• Language: english
• Publication type: Scientific paper - Original scientific paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Published version
• Journal title: The FEBS Journal
• Numbering: vol. 287, no. 21, pp. 4783-4800
• p-ISSN: 1742-464X
• e-ISSN: 1742-4658
• DOI: https://doi.org/10.1111/febs.15248
• URN:NBN: urn:nbn:hr:105:566790
• Publication: 2020-11
• Document URL: https://onlinelibrary.wiley.com/doi/10.1111/febs.15248
• Type of resource: Text
• Access conditions: Open access
• Created on: 2021-03-22 12:26:35