Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines

Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeut...

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Autores principales:	Sylwia K. Król, Ewa Bębenek, Magdalena Dmoszyńska-Graniczka, Adrianna Sławińska-Brych, Stanisław Boryczka, Andrzej Stepulak
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	acetylenic synthetic betulin derivatives ADMET betulin chemotherapy cisplatin druglikeness Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/ba5e1d6c4a214d36af98357814decfc0
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spelling	oai:doaj.org-article:ba5e1d6c4a214d36af98357814decfc02021-11-25T17:55:11ZAcetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines10.3390/ijms2222122991422-00671661-6596https://doaj.org/article/ba5e1d6c4a214d36af98357814decfc02021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12299https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G<sub>2</sub> phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.Sylwia K. KrólEwa BębenekMagdalena Dmoszyńska-GraniczkaAdrianna Sławińska-BrychStanisław BoryczkaAndrzej StepulakMDPI AGarticleacetylenic synthetic betulin derivativesADMETbetulinchemotherapycisplatindruglikenessBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12299, p 12299 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acetylenic synthetic betulin derivatives ADMET betulin chemotherapy cisplatin druglikeness Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	acetylenic synthetic betulin derivatives ADMET betulin chemotherapy cisplatin druglikeness Biology (General) QH301-705.5 Chemistry QD1-999 Sylwia K. Król Ewa Bębenek Magdalena Dmoszyńska-Graniczka Adrianna Sławińska-Brych Stanisław Boryczka Andrzej Stepulak Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
description	Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G<sub>2</sub> phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.
format	article
author	Sylwia K. Król Ewa Bębenek Magdalena Dmoszyńska-Graniczka Adrianna Sławińska-Brych Stanisław Boryczka Andrzej Stepulak
author_facet	Sylwia K. Król Ewa Bębenek Magdalena Dmoszyńska-Graniczka Adrianna Sławińska-Brych Stanisław Boryczka Andrzej Stepulak
author_sort	Sylwia K. Król
title	Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
title_short	Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
title_full	Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
title_fullStr	Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
title_full_unstemmed	Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
title_sort	acetylenic synthetic betulin derivatives inhibit akt and erk kinases activity, trigger apoptosis and suppress proliferation of neuroblastoma and rhabdomyosarcoma cell lines
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ba5e1d6c4a214d36af98357814decfc0
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Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines

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