New inhibitor of the TAp73 interaction with MDM2 and mutant p53
with promising antitumor activity against neuroblastoma

J 2019

New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma

GOMES, Sara, Liliana Sofia Gomes RAIMUNDO, Joana SOARES, Joana B. LOUREIRO, Mariana LEAO et. al.

Basic information

Original name

New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma

Authors

GOMES, Sara (620 Portugal), Liliana Sofia Gomes RAIMUNDO (620 Portugal), Joana SOARES (620 Portugal), Joana B. LOUREIRO (620 Portugal), Mariana LEAO (620 Portugal), Helena Isabel NOGUEIRA RAMOS ROCHA (620 Portugal), Madalena N. MONTEIRO (620 Portugal), Agostinho LEMOS (620 Portugal), Joana MOREIRA (620 Portugal), Madalena PINTO (620 Portugal), Petr CHLAPEK (203 Czech Republic, belonging to the institution), Renata VESELSKÁ (203 Czech Republic, belonging to the institution), Emília SOUSA (620 Portugal) and Lucília SARAIVA (620 Portugal, guarantor)

Edition

Cancer Letters, County Clare, ELSEVIER IRELAND LTD, 2019, 0304-3835

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Full Text

Impact factor

Impact factor: 7.360

RIV identification code

RIV/00216224:14310/19:00109297

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1016/j.canlet.2019.01.014

UT WoS

000458940700009

Keywords in English

p73; Carbaldehydic xanthone; Anticancer therapy

Abstract

V originále

TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.

Links

MUNI/A/0824/2017, interní kód MU

Name: Podpora výzkumné činnosti studentů molekulární biologie a genetiky 6 (Acronym: MolBiolGen)

Investor: Masaryk University, Category A

Citovat

GOMES, Sara, Liliana Sofia Gomes RAIMUNDO, Joana SOARES, Joana B. LOUREIRO, Mariana LEAO, Helena Isabel NOGUEIRA RAMOS ROCHA, Madalena N. MONTEIRO, Agostinho LEMOS, Joana MOREIRA, Madalena PINTO, Petr CHLAPEK, Renata VESELSKÁ, Emília SOUSA and Lucília SARAIVA. New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma. Cancer Letters. County Clare: ELSEVIER IRELAND LTD, 2019, vol. 446, No 4, p. 90-102. ISSN 0304-3835. Available from: https://dx.doi.org/10.1016/j.canlet.2019.01.014.

@article{1506137,
   author = {Gomes, Sara and Raimundo, Liliana Sofia Gomes and Soares, Joana and Loureiro, Joana B. and Leao, Mariana and Nogueira Ramos Rocha, Helena Isabel and Monteiro, Madalena N. and Lemos, Agostinho and Moreira, Joana and Pinto, Madalena and Chlapek, Petr and Veselská, Renata and Sousa, Emília and Saraiva, Lucília},
   article_location = {County Clare},
   article_number = {4},
   doi = {http://dx.doi.org/10.1016/j.canlet.2019.01.014},
   keywords = {p73; Carbaldehydic xanthone; Anticancer therapy},
   language = {eng},
   issn = {0304-3835},
   journal = {Cancer Letters},
   title = {New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma},
   url = {https://www.sciencedirect.com/science/article/pii/S0304383519300266},
   volume = {446},
   year = {2019}
}

TY  - JOUR
ID  - 1506137
AU  - Gomes, Sara - Raimundo, Liliana Sofia Gomes - Soares, Joana - Loureiro, Joana B. - Leao, Mariana - Nogueira Ramos Rocha, Helena Isabel - Monteiro, Madalena N. - Lemos, Agostinho - Moreira, Joana - Pinto, Madalena - Chlapek, Petr - Veselská, Renata - Sousa, Emília - Saraiva, Lucília
PY  - 2019
TI  - New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma
JF  - Cancer Letters
VL  - 446
IS  - 4
SP  - 90-102
EP  - 90-102
PB  - ELSEVIER IRELAND LTD
SN  - 03043835
KW  - p73
KW  - Carbaldehydic xanthone
KW  - Anticancer therapy
UR  - https://www.sciencedirect.com/science/article/pii/S0304383519300266
L2  - https://www.sciencedirect.com/science/article/pii/S0304383519300266
N2  - TAp73 is a key tumor suppressor protein, regulating the transcription of unique and shared p53 target genes with crucial roles in tumorigenesis and therapeutic response. As such, in tumors with impaired p53 signaling, like neuroblastoma, TAp73 activation represents an encouraging strategy, alternative to p53 activation, to suppress tumor growth and chemoresistance. In this work, we report a new TAp73-activating agent, the 1-carbaldehyde-3,4-dimethoxyxanthone (LEM2), with potent antitumor activity. Notably, LEM2 was able to release TAp73 from its interaction with both MDM2 and mutant p53, enhancing TAp73 transcriptional activity, cell cycle arrest, and apoptosis in p53-null and mutant p53-expressing tumor cells. Importantly, LEM2 displayed potent antitumor activity against patient-derived neuroblastoma cells, consistent with an activation of the TAp73 pathway. Additionally, potent synergistic effects were obtained for the combination of LEM2 with doxorubicin and cisplatin in patient-derived neuroblastoma cells. Collectively, besides its relevant contribution to the advance of TAp73 pharmacology, LEM2 may pave the way to improved therapeutic alternatives against neuroblastoma.
ER  -

GOMES, Sara, Liliana Sofia Gomes RAIMUNDO, Joana SOARES, Joana B. LOUREIRO, Mariana LEAO, Helena Isabel NOGUEIRA RAMOS ROCHA, Madalena N. MONTEIRO, Agostinho LEMOS, Joana MOREIRA, Madalena PINTO, Petr CHLAPEK, Renata VESELSKÁ, Emília SOUSA and Lucília SARAIVA. New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma. \textit{Cancer Letters}. County Clare: ELSEVIER IRELAND LTD, 2019, vol.~446, No~4, p.~90-102. ISSN~0304-3835. Available from: https://dx.doi.org/10.1016/j.canlet.2019.01.014.

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