Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells

Shabnaz Koochakkhani; Daniela S.N. Branco; Anxo Vila Alonso; Akshaya Murugesan; Puja Sarkar; Carina J.N. Caires; Sandhanasamy Devanesan; Mohamad S. AlSalhi; Nuno R. Candeias; Meenakshisundaram Kandhavelu

doi:10.1016/j.ejps.2024.106842

Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells

Shabnaz Koochakkhani
, Daniela S.N. Branco
, Anxo Vila Alonso
, Akshaya Murugesan
, Puja Sarkar
, Carina J.N. Caires
, Sandhanasamy Devanesan
, Mohamad S. AlSalhi
, Nuno R. Candeias^*
, Meenakshisundaram Kandhavelu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

4 Citations (Scopus)

55 Downloads (Pure)

Abstract

Current treatment for Glioblastoma Multiforme (GBM) is not efficient due to its aggressive nature, tendency to infiltrate surrounding brain tissue, and chemotherapy resistance. Tetrahydroquinoline scaffolds are emerging as a new class of drug for treating many human cancers including GBM. This study investigates the cytotoxicity effect of eight novel derivatives of 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol, containing substitute 1 with reduced dihydroquinoline fused with cyclohexene ring and substitute 2 with phenyl and methyl group. The 4-position of the aryl ring was determinant for the desired cytotoxicity, and out of the 8 synthesized compounds, the 4-trifluoromethyl substituted derivative (4ag) exhibited the most anti-GBM potential effect compared to the standard chemotherapeutic agent, temozolomide (TMZ), with IC₅₀ values of 38.3 μM and 40.6 μM in SNB19 and LN229 cell lines, respectively. Our results demonstrated that 4ag triggers apoptosis through the activation of Caspase-3/7. In addition, 4ag induced intracellular reactive oxygen species (iROS) which in turn elevated mitochondrial ROS (mtROS) and causes the disruption of the mitochondrial membrane potential (Δψmt) in both GBM cells. This compound also exhibited anti-migratory properties over the time in both the cell lines. Overall, these findings suggest that tetrahydroquinoline derivative, 4ag could lead to the development of a new drug for treating GBM.

Original language	English
Article number	106842
Journal	European Journal of Pharmaceutical Sciences
Volume	200
DOIs	https://doi.org/10.1016/j.ejps.2024.106842
Publication status	Published - 1 Sept 2024
Publication type	A1 Journal article-refereed

Funding

N.R.C. thanks the FCT (Funda\u00E7\u00E3o para a Ci\u00EAncia e Tecnologia) for funding through the Scientific Employment Stimulus (no. CEECINST/00026/2018). This work received support from the PT national funds (FCT/MCTES, Funda\u00E7\u00E3o para a Ci\u0109ncia e Tecnologia and Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior) through the project nos. UIDB/50006/2020, UIDP/50006/2020, and PTDC/QUI-QOR/1131/2020. The authors express their sincere appreciation to the Researchers Supporting Project Number (RSP2024R398) King Saud University, Riyadh, Saudi Arabia.

Funders	Funder number
Fundação para a Ciência e a Tecnologia
King Saud University
MCTES
Scientific Employment Stimulus	CEECINST/00026/2018
Ministério da Ciência, Tecnologia e Ensino Superior	RSP2024R398, UIDP/50006/2020, UIDB/50006/2020, PTDC/QUI-QOR/1131/2020
Ministério da Ciência, Tecnologia e Ensino Superior

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Apoptosis
Cytotoxicity
Glioblastoma multiforme
Reactive oxygen species
Tetrahydroquinoline derivatives

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

Pharmaceutical Science

Access to Document

10.1016/j.ejps.2024.106842Licence: CC BY

1-s2.0-S0928098724001544-mainFinal published version, 4.15 MBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202408128043Licence: CC BY

Cite this

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title = "Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells",

abstract = "Current treatment for Glioblastoma Multiforme (GBM) is not efficient due to its aggressive nature, tendency to infiltrate surrounding brain tissue, and chemotherapy resistance. Tetrahydroquinoline scaffolds are emerging as a new class of drug for treating many human cancers including GBM. This study investigates the cytotoxicity effect of eight novel derivatives of 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol, containing substitute 1 with reduced dihydroquinoline fused with cyclohexene ring and substitute 2 with phenyl and methyl group. The 4-position of the aryl ring was determinant for the desired cytotoxicity, and out of the 8 synthesized compounds, the 4-trifluoromethyl substituted derivative (4ag) exhibited the most anti-GBM potential effect compared to the standard chemotherapeutic agent, temozolomide (TMZ), with IC50 values of 38.3 μM and 40.6 μM in SNB19 and LN229 cell lines, respectively. Our results demonstrated that 4ag triggers apoptosis through the activation of Caspase-3/7. In addition, 4ag induced intracellular reactive oxygen species (iROS) which in turn elevated mitochondrial ROS (mtROS) and causes the disruption of the mitochondrial membrane potential (Δψmt) in both GBM cells. This compound also exhibited anti-migratory properties over the time in both the cell lines. Overall, these findings suggest that tetrahydroquinoline derivative, 4ag could lead to the development of a new drug for treating GBM.",

keywords = "Apoptosis, Cytotoxicity, Glioblastoma multiforme, Reactive oxygen species, Tetrahydroquinoline derivatives",

author = "Shabnaz Koochakkhani and Branco, \{Daniela S.N.\} and Alonso, \{Anxo Vila\} and Akshaya Murugesan and Puja Sarkar and Caires, \{Carina J.N.\} and Sandhanasamy Devanesan and AlSalhi, \{Mohamad S.\} and Candeias, \{Nuno R.\} and Meenakshisundaram Kandhavelu",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = sep,

day = "1",

doi = "10.1016/j.ejps.2024.106842",

language = "English",

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T1 - Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells

AU - Koochakkhani, Shabnaz

AU - Branco, Daniela S.N.

AU - Alonso, Anxo Vila

AU - Murugesan, Akshaya

AU - Sarkar, Puja

AU - Caires, Carina J.N.

AU - Devanesan, Sandhanasamy

AU - AlSalhi, Mohamad S.

AU - Candeias, Nuno R.

AU - Kandhavelu, Meenakshisundaram

PY - 2024/9/1

Y1 - 2024/9/1

N2 - Current treatment for Glioblastoma Multiforme (GBM) is not efficient due to its aggressive nature, tendency to infiltrate surrounding brain tissue, and chemotherapy resistance. Tetrahydroquinoline scaffolds are emerging as a new class of drug for treating many human cancers including GBM. This study investigates the cytotoxicity effect of eight novel derivatives of 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol, containing substitute 1 with reduced dihydroquinoline fused with cyclohexene ring and substitute 2 with phenyl and methyl group. The 4-position of the aryl ring was determinant for the desired cytotoxicity, and out of the 8 synthesized compounds, the 4-trifluoromethyl substituted derivative (4ag) exhibited the most anti-GBM potential effect compared to the standard chemotherapeutic agent, temozolomide (TMZ), with IC50 values of 38.3 μM and 40.6 μM in SNB19 and LN229 cell lines, respectively. Our results demonstrated that 4ag triggers apoptosis through the activation of Caspase-3/7. In addition, 4ag induced intracellular reactive oxygen species (iROS) which in turn elevated mitochondrial ROS (mtROS) and causes the disruption of the mitochondrial membrane potential (Δψmt) in both GBM cells. This compound also exhibited anti-migratory properties over the time in both the cell lines. Overall, these findings suggest that tetrahydroquinoline derivative, 4ag could lead to the development of a new drug for treating GBM.

AB - Current treatment for Glioblastoma Multiforme (GBM) is not efficient due to its aggressive nature, tendency to infiltrate surrounding brain tissue, and chemotherapy resistance. Tetrahydroquinoline scaffolds are emerging as a new class of drug for treating many human cancers including GBM. This study investigates the cytotoxicity effect of eight novel derivatives of 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol, containing substitute 1 with reduced dihydroquinoline fused with cyclohexene ring and substitute 2 with phenyl and methyl group. The 4-position of the aryl ring was determinant for the desired cytotoxicity, and out of the 8 synthesized compounds, the 4-trifluoromethyl substituted derivative (4ag) exhibited the most anti-GBM potential effect compared to the standard chemotherapeutic agent, temozolomide (TMZ), with IC50 values of 38.3 μM and 40.6 μM in SNB19 and LN229 cell lines, respectively. Our results demonstrated that 4ag triggers apoptosis through the activation of Caspase-3/7. In addition, 4ag induced intracellular reactive oxygen species (iROS) which in turn elevated mitochondrial ROS (mtROS) and causes the disruption of the mitochondrial membrane potential (Δψmt) in both GBM cells. This compound also exhibited anti-migratory properties over the time in both the cell lines. Overall, these findings suggest that tetrahydroquinoline derivative, 4ag could lead to the development of a new drug for treating GBM.

KW - Apoptosis

KW - Cytotoxicity

KW - Glioblastoma multiforme

KW - Reactive oxygen species

KW - Tetrahydroquinoline derivatives

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DO - 10.1016/j.ejps.2024.106842

M3 - Article

C2 - 38936514

AN - SCOPUS:85197102434

SN - 0928-0987

VL - 200

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

M1 - 106842

ER -

Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells

Abstract

Funding

UN SDGs

Keywords

Publication forum classification

ASJC Scopus subject areas

Access to Document

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