AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway
Colorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, (<i>E</i>)-1′-((4-bromobenzylidene)amino)-5′-oxo-1′,5′-dihydro-10<i>H</i>-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-19), showed significant cytotoxicity in HCT-116 col...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-11-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/29/22/5344 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850267082486185984 |
|---|---|
| author | Valgrícia Matias de Sousa Sâmia Sousa Duarte Rafael Carlos Ferreira Natália Ferreira de Sousa Marcus Tullius Scotti Luciana Scotti Marcelo Sobral da Silva Josean Fechine Tavares Ricardo Olímpio de Moura Juan Carlos Ramos Gonçalves Marianna Vieira Sobral |
| author_facet | Valgrícia Matias de Sousa Sâmia Sousa Duarte Rafael Carlos Ferreira Natália Ferreira de Sousa Marcus Tullius Scotti Luciana Scotti Marcelo Sobral da Silva Josean Fechine Tavares Ricardo Olímpio de Moura Juan Carlos Ramos Gonçalves Marianna Vieira Sobral |
| author_sort | Valgrícia Matias de Sousa |
| collection | DOAJ |
| description | Colorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, (<i>E</i>)-1′-((4-bromobenzylidene)amino)-5′-oxo-1′,5′-dihydro-10<i>H</i>-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-19), showed significant cytotoxicity in HCT-116 colorectal carcinoma cells (half maximal inhibitory concentration, IC50 = 10.35 ± 1.66 µM) and antioxidant effects after 48 h of treatment. In this study, Molegro Virtual Docker v.6.0.1 software was used to investigate the interactions between AMTAC-19 and the Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), and p38 Mitogen-Activated Protein Kinase α (p38α MAPK). In vitro assays were conducted in HCT-116 cells to evaluate the effect of AMTAC-19 on the modulation of these proteins’ activities using flow cytometry. Furthermore, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence or absence of ERK1/2, JNK, and p38 MAPK inhibitors was used to evaluate the involvement of these enzymes in AMTAC-19 cytotoxicity. ROS production was assessed using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay at various incubation times (30 min, 1 h, 6 h, 12 h, and 24 h), and the MTT assay using N-acetyl-L-cysteine (NAC) was performed. In silico results indicated that AMTAC-19 interacts with ERK1, JNK1, and p38α MAPK. Additionally, AMTAC-19 activated ERK1/2 and JNK1 in HCT-116 cells, and its cytotoxicity was significantly reduced in the presence of ERK1/2 and JNK inhibitors. AMTAC-19 also induced a significant increase in ROS production (30 min and 1 h), while NAC pretreatment reduced its cytotoxicity. These findings support AMTAC-19′s in vitro antitumor effect through ROS-dependent activation of ERK and JNK pathways. |
| format | Article |
| id | doaj-art-139f568071074f7ebd084358d9fc985d |
| institution | OA Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-139f568071074f7ebd084358d9fc985d2025-08-20T01:53:57ZengMDPI AGMolecules1420-30492024-11-012922534410.3390/molecules29225344AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling PathwayValgrícia Matias de Sousa0Sâmia Sousa Duarte1Rafael Carlos Ferreira2Natália Ferreira de Sousa3Marcus Tullius Scotti4Luciana Scotti5Marcelo Sobral da Silva6Josean Fechine Tavares7Ricardo Olímpio de Moura8Juan Carlos Ramos Gonçalves9Marianna Vieira Sobral10Postgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilDrug Development and Synthesis Laboratory, Department of Pharmacy, State University of Paraíba, João Pessoa 58070-450, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilPostgraduate Program in Natural Products and Bioactive Synthetics, Federal University of Paraíba, João Pessoa 58051-970, PB, BrazilColorectal cancer remains a significant cause of mortality worldwide. A spiro-acridine derivative, (<i>E</i>)-1′-((4-bromobenzylidene)amino)-5′-oxo-1′,5′-dihydro-10<i>H</i>-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-19), showed significant cytotoxicity in HCT-116 colorectal carcinoma cells (half maximal inhibitory concentration, IC50 = 10.35 ± 1.66 µM) and antioxidant effects after 48 h of treatment. In this study, Molegro Virtual Docker v.6.0.1 software was used to investigate the interactions between AMTAC-19 and the Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), and p38 Mitogen-Activated Protein Kinase α (p38α MAPK). In vitro assays were conducted in HCT-116 cells to evaluate the effect of AMTAC-19 on the modulation of these proteins’ activities using flow cytometry. Furthermore, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in the presence or absence of ERK1/2, JNK, and p38 MAPK inhibitors was used to evaluate the involvement of these enzymes in AMTAC-19 cytotoxicity. ROS production was assessed using the 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) assay at various incubation times (30 min, 1 h, 6 h, 12 h, and 24 h), and the MTT assay using N-acetyl-L-cysteine (NAC) was performed. In silico results indicated that AMTAC-19 interacts with ERK1, JNK1, and p38α MAPK. Additionally, AMTAC-19 activated ERK1/2 and JNK1 in HCT-116 cells, and its cytotoxicity was significantly reduced in the presence of ERK1/2 and JNK inhibitors. AMTAC-19 also induced a significant increase in ROS production (30 min and 1 h), while NAC pretreatment reduced its cytotoxicity. These findings support AMTAC-19′s in vitro antitumor effect through ROS-dependent activation of ERK and JNK pathways.https://www.mdpi.com/1420-3049/29/22/5344colorectal carcinomaoxidative stressMAPKs |
| spellingShingle | Valgrícia Matias de Sousa Sâmia Sousa Duarte Rafael Carlos Ferreira Natália Ferreira de Sousa Marcus Tullius Scotti Luciana Scotti Marcelo Sobral da Silva Josean Fechine Tavares Ricardo Olímpio de Moura Juan Carlos Ramos Gonçalves Marianna Vieira Sobral AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway Molecules colorectal carcinoma oxidative stress MAPKs |
| title | AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway |
| title_full | AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway |
| title_fullStr | AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway |
| title_full_unstemmed | AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway |
| title_short | AMTAC-19, a Spiro-Acridine Compound, Induces In Vitro Antitumor Effect via the ROS-ERK/JNK Signaling Pathway |
| title_sort | amtac 19 a spiro acridine compound induces in vitro antitumor effect via the ros erk jnk signaling pathway |
| topic | colorectal carcinoma oxidative stress MAPKs |
| url | https://www.mdpi.com/1420-3049/29/22/5344 |
| work_keys_str_mv | AT valgriciamatiasdesousa amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT samiasousaduarte amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT rafaelcarlosferreira amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT nataliaferreiradesousa amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT marcustulliusscotti amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT lucianascotti amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT marcelosobraldasilva amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT joseanfechinetavares amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT ricardoolimpiodemoura amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT juancarlosramosgoncalves amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway AT mariannavieirasobral amtac19aspiroacridinecompoundinducesinvitroantitumoreffectviatheroserkjnksignalingpathway |