A ROS-mediated lysosomal-mitochondrial pathway is induced by a novel Amonafide analogue, 7c, in human Hela cervix
Ke Shen1, Liyun Sun, Huanying Zhang
1State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237, PR China.
Abstract:
In this study, a novel naphthalimide derivative 7c was designed which is topo II inhibiting though owning weak DNA binders. It was shown that 7c could induce cancer cells apoptosis and have less cytotoxicity in normal human cell. Further investigations on Hela cells revealed that 7c could also induce ROS generation, lysosome rupture as well as cathepsin B release. Subsequent mitochondrial damages including mitochondrial membrane permeabilization and the release of cytochrome c were also found in 7c when treating with Hela cells. According to our data, 7c may act as a lead compound for potential anticancer drugs. The idea of naphthalimides modification may also provide a novel strategy for naphthalimides design.
Insights
A novel naphthalimide derivative, 7c, shows promise as an anticancer drug by inducing cancer cell death and minimal harm to normal cells. This compound triggers apoptosis, ROS generation, and mitochondrial damage in cancer cells.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Naphthalimide derivatives are explored for anticancer properties.
- Targeting topoisomerase II (topo II) is a validated anticancer strategy.
- Developing novel compounds with improved efficacy and reduced toxicity is crucial.
Purpose of the Study:
- To design and evaluate a novel naphthalimide derivative (7c) as a potential anticancer agent.
- To investigate the mechanism of action of 7c in cancer cells.
- To assess the therapeutic potential and safety profile of 7c.
Main Methods:
- Synthesis and characterization of naphthalimide derivative 7c.
- In vitro evaluation of cytotoxicity in cancer and normal human cells.
- Analysis of apoptosis induction, reactive oxygen species (ROS) generation, and lysosomal integrity.
- Assessment of mitochondrial damage, including membrane permeabilization and cytochrome c release.
Main Results:
- Compound 7c exhibits weak DNA binding but potent topoisomerase II (topo II) inhibition.
- 7c effectively induces apoptosis in cancer cells while demonstrating lower cytotoxicity in normal cells.
- Treatment with 7c leads to ROS generation, lysosome rupture, and cathepsin B release in Hela cells.
- Mitochondrial damage, evidenced by membrane permeabilization and cytochrome c release, is observed upon 7c treatment.
Conclusions:
- Naphthalimide derivative 7c shows significant potential as a lead compound for developing novel anticancer therapeutics.
- The mechanism of action involves inducing apoptosis through ROS generation, lysosomal disruption, and mitochondrial pathway activation.
- Naphthalimide modification presents a viable strategy for designing new anticancer agents.
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