Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477
Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro a...
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| Format: | Article |
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MDPI AG
2021-05-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/19/6/285 |
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| author | Sungmi Song Sua Kim Eslam R. El-Sawy Claudia Cerella Barbora Orlikova-Boyer Gilbert Kirsch Christo Christov Mario Dicato Marc Diederich |
| author_facet | Sungmi Song Sua Kim Eslam R. El-Sawy Claudia Cerella Barbora Orlikova-Boyer Gilbert Kirsch Christo Christov Mario Dicato Marc Diederich |
| author_sort | Sungmi Song |
| collection | DOAJ |
| description | Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia. |
| first_indexed | 2024-03-10T11:12:09Z |
| format | Article |
| id | doaj.art-57817b0540814cc78e3934b3af71d55f |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-03-10T11:12:09Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-57817b0540814cc78e3934b3af71d55f2023-11-21T20:43:24ZengMDPI AGMarine Drugs1660-33972021-05-0119628510.3390/md19060285Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477Sungmi Song0Sua Kim1Eslam R. El-Sawy2Claudia Cerella3Barbora Orlikova-Boyer4Gilbert Kirsch5Christo Christov6Mario Dicato7Marc Diederich8Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08626, KoreaDepartment of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08626, KoreaChemistry Department of Natural Compounds, National Research Centre, Dokki, 12622 Giza, EgyptDepartment of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08626, KoreaDepartment of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08626, KoreaUMR CNRS 7565 SRSMC, Université du Lorraine, 57070 Metz, FranceService d’Histologie, Faculté de Médicine, Université de Lorraine, INSERM U1256 NGERE, 54000 Nancy, FranceLaboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, Rue Edward Steichen, 2540 Luxembourg, LuxembourgDepartment of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08626, KoreaAplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.https://www.mdpi.com/1660-3397/19/6/285aplysinopsin analogsindole alkaloidsmarine sourcechronic myeloid leukemiaBH3 mimetics |
| spellingShingle | Sungmi Song Sua Kim Eslam R. El-Sawy Claudia Cerella Barbora Orlikova-Boyer Gilbert Kirsch Christo Christov Mario Dicato Marc Diederich Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477 Marine Drugs aplysinopsin analogs indole alkaloids marine source chronic myeloid leukemia BH3 mimetics |
| title | Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477 |
| title_full | Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477 |
| title_fullStr | Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477 |
| title_full_unstemmed | Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477 |
| title_short | Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477 |
| title_sort | anti leukemic properties of aplysinopsin derivative ee 84 alone and combined to bh3 mimetic a 1210477 |
| topic | aplysinopsin analogs indole alkaloids marine source chronic myeloid leukemia BH3 mimetics |
| url | https://www.mdpi.com/1660-3397/19/6/285 |
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