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New Sinomenine Derivative as a Potential Drug for Cervical Cancer via Inducing Ferroptosis
Yifan Shang1, Keran Li1, Wenting Liu1
1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China.
Abstract:
Cervical cancer remains a serious threat to women's health due to chemotherapy resistance, poor prognosis, and survival rates. Novel anti-cervical cancer agents are urgently needed. Sinomenine derivatives, which were prepared from sinomenine (a natural morphinane alkaloid), have been previously reported by us to be cytotoxic toward various cancer cell lines. Also, an increase in ROS production, which is associated with ferroptosis, was observed in cancer cells. In this study, we synthesized 18 sinomenine derivatives and evaluated their antitumor activity in vitro against four human tumor cell lines (HeLa, HepG2, A549, and HT-29). Five derivatives (12-16) containing quinoline fragments showed broad-spectrum antitumor activity. Significantly, 16 showed specific activity against HeLa and HT-29 cells, with IC50 values of 5.60 and 7.60 μM, respectively. Its optimal lipophilicity (-1 < log P < 2) likely contributes to this efficacy. Further study in vitro showed that Derivative 16 could increase the accumulation of ferrous iron, which caused an increase in ROS levels and MDA contents, and a decrease in GPX4 activity. Western blot results showed that 16 decreased the FHTI-to-GAPDH, SLC7A11-to-GAPDH, and GPX4-to-GAPDH ratios. Molecular docking simulation results suggested that 16 can interact with ferroptosis-related proteins via the van der Waals force, and cation-π, anion-π, and hydrogen bonding interactions. In brief, Compound 16 may be a potentially useful drug for the treatment of cervical cancer, as it induces ferroptosis in HeLa cells by inhibiting FTH1 expression and the SLC7A11/GSH/GPX4 pathway.
Insights
Novel sinomenine derivatives show promise against cervical cancer. Compound 16 effectively induces cell death via ferroptosis, offering a potential new treatment strategy for this disease.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Cervical cancer poses a significant global health challenge, characterized by treatment resistance and low survival rates.
- Existing therapies are limited, necessitating the development of novel anti-cancer agents.
- Sinomenine derivatives, previously shown to be cytotoxic, are explored for their anti-cancer potential.
Purpose of the Study:
- To synthesize and evaluate novel sinomenine derivatives for antitumor activity.
- To identify specific derivatives with potent and selective anti-cervical cancer effects.
- To elucidate the mechanism of action of promising derivatives, focusing on ferroptosis.
Main Methods:
- Synthesis of 18 sinomenine derivatives from sinomenine.
- In vitro evaluation of antitumor activity against HeLa, HepG2, A549, and HT-29 cell lines.
- In vitro assays to assess ferroptosis induction, including reactive oxygen species (ROS) and malondialdehyde (MDA) levels, glutathione peroxidase 4 (GPX4) activity, and protein expression via Western blot.
- Molecular docking simulations to predict interactions with ferroptosis-related proteins.
Main Results:
- Five derivatives (12-16) exhibited broad-spectrum antitumor activity.
- Derivative 16 demonstrated significant and specific cytotoxicity against HeLa and HT-29 cells (IC50 values 5.60 and 7.60 μM, respectively).
- Derivative 16 induced ferroptosis by increasing cellular iron, ROS, and MDA, while decreasing GPX4 activity and inhibiting FTH1 and SLC7A11 expression.
- Molecular docking indicated favorable interactions between Derivative 16 and ferroptosis-related proteins.
Conclusions:
- Sinomenine derivative 16 is a potent anti-cervical cancer agent with specific activity against HeLa and HT-29 cells.
- Derivative 16 induces ferroptosis in cervical cancer cells by targeting the FTH1 and SLC7A11/GSH/GPX4 pathway.
- Compound 16 represents a promising lead for the development of novel cervical cancer therapeutics.
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