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Embryo‐derived teratoma in vitro biological system reveals antitumor and embryotoxic activity of valproate
Author(s) -
Plazibat Milvija,
Katušić Bojanac Ana,
Himerleich Perić Marta,
Gamulin Ozren,
Rašić Mario,
Radonić Vedran,
Škrabić Marko,
Krajačić Maria,
Krasić Jure,
Sinčić Nino,
JurićLekić Gordana,
Balarin Maja,
BulićJakuš Floriana
Publication year - 2020
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15248
Subject(s) - teratocarcinoma , teratoma , embryo , biology , in vitro , in vivo , epigenetics , chemistry , cancer research , andrology , microbiology and biotechnology , pathology , medicine , cellular differentiation , biochemistry , genetics , gene
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 m m VPA . 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(CH 3 )/A(CH 2 )]) with apoptotic biomarkers within the amide I region for β‐sheets, and unordered and CH 2 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.