Non-DHFR-mediated effects of methotrexate in osteosarcoma cell
lines: epigenetic alterations and enhanced cell differentiation

J 2016

Non-DHFR-mediated effects of methotrexate in osteosarcoma cell lines: epigenetic alterations and enhanced cell differentiation

ŠRÁMEK, Martin, Jakub NERADIL, Jaroslav ŠTĚRBA and Renata VESELSKÁ

Basic information

Original name

Non-DHFR-mediated effects of methotrexate in osteosarcoma cell lines: epigenetic alterations and enhanced cell differentiation

Authors

ŠRÁMEK, Martin (203 Czech Republic, belonging to the institution), Jakub NERADIL (203 Czech Republic, belonging to the institution), Jaroslav ŠTĚRBA (203 Czech Republic, belonging to the institution) and Renata VESELSKÁ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Cancer Cell International, London, BioMed Central, 2016, 1475-2867

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30209 Paediatrics

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 2.740

RIV identification code

RIV/00216224:14110/16:00088886

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1186/s12935-016-0289-2

UT WoS

000371005700001

Keywords in English

methotrexate;osteosarcoma;epigenetic regulation;DNA methylation;histone acetylation;all-trans retinoic acid;osteogenic differentiation

Abstract

V originále

Methotrexate is an important chemotherapeutic drug widely known as an inhibitor of dihydrofolate reductase (DHFR) which inhibits the reduction of folic acid. DHFR-mediated effects are apparently responsible for its primary antineoplastic action. However, other non-DHFR-mediated effects of methotrexate have been recently discovered, which might be very useful in the development of new strategies for the treatment of pediatric malignancies. The principal goal of this study was to analyze the possible impact of clinically achievable methotrexate levels on cell proliferation, mechanisms of epigenetic regulation (DNA methylation and histone acetylation), induced differentiation and the expression of differentiation-related genes in six osteosarcoma cell lines. Methotrexate significantly decreased the proliferation of Saos-2 cells exclusively, suggesting that this reference cell line was sensitive to the DHFR-mediated effects of methotrexate. In contrast, other results indicated non-DHFR-mediated effects in patient-derived cell lines. Methotrexate-induced DNA demethylation was detected in almost all of them; methotrexate was able to lower the level of 5-methylcytosine in treated cells, and this effect was similar to the effect of 5-aza-2'-deoxycytidine. Furthermore, methotrexate increased the level of acetylated histone H3 in the OSA-06 cell line. Methotrexate also enhanced all-trans retinoic acid-induced cell differentiation in three patient-derived osteosarcoma cell lines, and the modulation of expression of the differentiation-related genes was also shown. Overall non-DHFR-mediated effects of methotrexate were detected in the patient-derived osteosarcoma cell lines. Methotrexate acts as an epigenetic modifier and has a potential impact on cell differentiation and the expression of related genes. Furthermore, the combination of methotrexate and all-trans retinoic acid can be effective as a differentiation therapy for osteosarcoma.

Links

NT14327, research and development project

Name: DHFR- a non-DHFR-mediované účinky metotrexátu na buněčné úrovni: studie na liniích solidních nádorů dětského věku

Investor: Ministry of Health of the CR

Citovat

ŠRÁMEK, Martin, Jakub NERADIL, Jaroslav ŠTĚRBA and Renata VESELSKÁ. Non-DHFR-mediated effects of methotrexate in osteosarcoma cell lines: epigenetic alterations and enhanced cell differentiation. Cancer Cell International. London: BioMed Central, 2016, vol. 16, No 14, p. "nestránkováno", 12 pp. ISSN 1475-2867. Available from: https://dx.doi.org/10.1186/s12935-016-0289-2.

@article{1354614,
   author = {Šrámek, Martin and Neradil, Jakub and Štěrba, Jaroslav and Veselská, Renata},
   article_location = {London},
   article_number = {14},
   doi = {http://dx.doi.org/10.1186/s12935-016-0289-2},
   keywords = {methotrexate;osteosarcoma;epigenetic regulation;DNA methylation;histone acetylation;all-trans retinoic acid;osteogenic differentiation},
   language = {eng},
   issn = {1475-2867},
   journal = {Cancer Cell International},
   title = {Non-DHFR-mediated effects of methotrexate in osteosarcoma cell lines: epigenetic alterations and enhanced cell differentiation},
   url = {http://cancerci.biomedcentral.com/articles/10.1186/s12935-016-0289-2},
   volume = {16},
   year = {2016}
}

TY  - JOUR
ID  - 1354614
AU  - Šrámek, Martin - Neradil, Jakub - Štěrba, Jaroslav - Veselská, Renata
PY  - 2016
TI  - Non-DHFR-mediated effects of methotrexate in osteosarcoma cell lines: epigenetic alterations and enhanced cell differentiation
JF  - Cancer Cell International
VL  - 16
IS  - 14
SP  - "nestránkováno"
EP  - "nestránkováno"
PB  - BioMed Central
SN  - 14752867
KW  - methotrexate;osteosarcoma;epigenetic regulation;DNA methylation;histone acetylation;all-trans retinoic acid;osteogenic differentiation
UR  - http://cancerci.biomedcentral.com/articles/10.1186/s12935-016-0289-2
N2  - Methotrexate is an important chemotherapeutic drug widely known as an inhibitor of dihydrofolate reductase (DHFR) which inhibits the reduction of folic acid. DHFR-mediated effects are apparently responsible for its primary antineoplastic action. However, other non-DHFR-mediated effects of methotrexate have been recently discovered, which might be very useful in the development of new strategies for the treatment of pediatric malignancies. The principal goal of this study was to analyze the possible impact of clinically achievable methotrexate levels on cell proliferation, mechanisms of epigenetic regulation (DNA methylation and histone acetylation), induced differentiation and the expression of differentiation-related genes in six osteosarcoma cell lines. Methotrexate significantly decreased the proliferation of Saos-2 cells exclusively, suggesting that this reference cell line was sensitive to the DHFR-mediated effects of methotrexate. In contrast, other results indicated non-DHFR-mediated effects in patient-derived cell lines. Methotrexate-induced DNA demethylation was detected in almost all of them; methotrexate was able to lower the level of 5-methylcytosine in treated cells, and this effect was similar to the effect of 5-aza-2'-deoxycytidine. Furthermore, methotrexate increased the level of acetylated histone H3 in the OSA-06 cell line. Methotrexate also enhanced all-trans retinoic acid-induced cell differentiation in three patient-derived osteosarcoma cell lines, and the modulation of expression of the differentiation-related genes was also shown. Overall non-DHFR-mediated effects of methotrexate were detected in the patient-derived osteosarcoma cell lines. Methotrexate acts as an epigenetic modifier and has a potential impact on cell differentiation and the expression of related genes. Furthermore, the combination of methotrexate and all-trans retinoic acid can be effective as a differentiation therapy for osteosarcoma.
ER  -

ŠRÁMEK, Martin, Jakub NERADIL, Jaroslav ŠTĚRBA and Renata VESELSKÁ. Non-DHFR-mediated effects of methotrexate in osteosarcoma cell lines: epigenetic alterations and enhanced cell differentiation. \textit{Cancer Cell International}. London: BioMed Central, 2016, vol.~16, No~14, p.~''nestránkováno'', 12 pp. ISSN~1475-2867. Available from: https://dx.doi.org/10.1186/s12935-016-0289-2.

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