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Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells
Shabnaz Koochakkhani1, Daniela S N Branco2, Anxo Vila Alonso3
1Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; BioMeditech and Tays Cancer Center, Tampere University, Hospital, P.O. Box 553, 33101 Tampere, Finland.
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.
Insights
A novel tetrahydroquinoline derivative, compound 4ag, shows significant potential against Glioblastoma Multiforme (GBM). This compound effectively combats GBM cells by inducing apoptosis and disrupting mitochondrial function, offering a promising new avenue for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Glioblastoma Multiforme (GBM) presents significant treatment challenges due to its aggressive nature, invasiveness, and resistance to chemotherapy.
- Tetrahydroquinoline scaffolds are an emerging class of compounds with potential applications in cancer therapy, including GBM.
Purpose of the Study:
- To synthesize and evaluate novel tetrahydroquinoline derivatives for their cytotoxic effects against Glioblastoma Multiforme (GBM) cell lines.
- To identify specific structural features that contribute to anti-GBM activity.
Main Methods:
- Synthesis of eight novel 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol derivatives.
- Assessment of cytotoxicity against SNB19 and LN229 GBM cell lines, comparing with temozolomide (TMZ).
- Investigation of apoptosis induction (Caspase-3/7 activation), reactive oxygen species (ROS) generation (iROS, mtROS), mitochondrial membrane potential disruption (Δψmt), and anti-migratory effects.
Main Results:
- The 4-trifluoromethyl substituted derivative (4ag) demonstrated the most potent anti-GBM activity, with IC50 values of 38.3 μM (SNB19) and 40.6 μM (LN229).
- Compound 4ag induced apoptosis via Caspase-3/7 activation and increased intracellular and mitochondrial ROS levels.
- 4ag also disrupted mitochondrial membrane potential and exhibited anti-migratory properties in GBM cells.
Conclusions:
- The tetrahydroquinoline derivative 4ag exhibits significant cytotoxic and anti-proliferative effects against GBM cells.
- 4ag's mechanism of action involves apoptosis induction, ROS generation, and mitochondrial dysfunction.
- These findings highlight 4ag as a promising candidate for the development of novel Glioblastoma Multiforme therapeutics.
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