In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:001169053300149&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3390/cancers15164136
eISSN
2072-6694
Externe Identifier
  • Clarivate Analytics Document Solution ID: IV2T4
Ausgabe der Veröffentlichung
16
Zeitschrift
CANCERS
Schlüsselwörter
  • drug repurposing
  • hematological malignancies
  • microtubules
  • programmed cell death
  • targeted chemotherapy
  • third-generation retinoid
  • xenograft tumor zebrafish model
Artikelnummer
ARTN 4136
Datum der Veröffentlichung
2023
Status
Published
Titel
In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia
Sub types
  • Article
Ausgabe der Zeitschrift
15

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:001056281900001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3390/cancers15164136
eISSN
2072-6694
Externe Identifier
  • Clarivate Analytics Document Solution ID: Q3AU2
  • PubMed Identifier: 37627164
Ausgabe der Veröffentlichung
16
Zeitschrift
CANCERS
Schlüsselwörter
  • drug repurposing
  • hematological malignancies
  • microtubules
  • programmed cell death
  • targeted chemotherapy
  • third-generation retinoid
  • xenograft tumor zebrafish model
Artikelnummer
ARTN 4136
Datum der Veröffentlichung
2023
Status
Published
Titel
In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia
Sub types
  • Article
Ausgabe der Zeitschrift
15

Data source: Web of Science (Lite)

Abstract
<jats:p>The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of −7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (Kd value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC50 = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC50, 1 × IC50, 2 × IC50) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G2/M phase and increased the portion of cells in the sub-G0/G1 phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.</jats:p>
Autoren
DOI
10.3390/cancers15164136
eISSN
2072-6694
Ausgabe der Veröffentlichung
16
Zeitschrift
Cancers
Sprache
en
Online publication date
2023
Paginierung
4136 - 4136
Status
Published online
Herausgeber
MDPI AG
Herausgeber URL
http://dx.doi.org/10.3390/cancers15164136
Datum der Datenerfassung
2023
Titel
In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia
Ausgabe der Zeitschrift
15

Data source: Crossref

Abstract
The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of -7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (K<sub>d</sub> value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC<sub>50</sub> = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC<sub>50</sub>, 1 × IC<sub>50</sub>, 2 × IC<sub>50</sub>) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G<sub>2</sub>/M phase and increased the portion of cells in the sub-G<sub>0</sub>/G<sub>1</sub> phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
DOI
10.3390/cancers15164136
eISSN
2072-6694
Externe Identifier
  • PubMed Identifier: 37627164
  • PubMed Central ID: PMC10452460
Funding acknowledgements
  • Marc Strobel: MS003
Open access
true
ISSN
2072-6694
Ausgabe der Veröffentlichung
16
Zeitschrift
Cancers
Sprache
eng
Medium
Electronic
Online publication date
2023
Open access status
Open Access
Paginierung
4136
Datum der Veröffentlichung
2023
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2023
Titel
In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
15

Files

https://europepmc.org/articles/PMC10452460?pdf=render

Data source: Europe PubMed Central

Abstract
The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of -7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (Kd value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC50 = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC50, 1 × IC50, 2 × IC50) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G2/M phase and increased the portion of cells in the sub-G0/G1 phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.
Date of acceptance
2023
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/37627164
DOI
10.3390/cancers15164136
Externe Identifier
  • PubMed Central ID: PMC10452460
Funding acknowledgements
  • Marc Strobel: MS003
ISSN
2072-6694
Ausgabe der Veröffentlichung
16
Zeitschrift
Cancers (Basel)
Schlüsselwörter
  • drug repurposing
  • hematological malignancies
  • microtubules
  • programmed cell death
  • targeted chemotherapy
  • third-generation retinoid
  • xenograft tumor zebrafish model
Sprache
eng
Country
Switzerland
PII
cancers15164136
Datum der Veröffentlichung
2023
Status
Published online
Titel
In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
15

Data source: PubMed

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