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In Vitro Anticancer Activity of Two Ferrocene-Containing Camphor Sulfonamides as Promising Agents against Lung Cancer
Maria Schröder1, Maria Petrova1, Zlatina Vlahova1
1Institute of Molecular Biology "Akad. Roumen Tsanev", Bulgarian Academy of Sciences, Acad. G. Bonchev Str, bl 21, 1113 Sofia, Bulgaria.
Abstract:
The successful design of antitumour drugs often combines in one molecule different biologically active subunits that can affect various regulatory pathways in the cell and thus achieve higher efficacy. Two ferrocene derivatives, DK-164 and CC-78, with different residues were tested for cytotoxic potential on non-small lung cancer cell lines, A549 and H1299, and non-cancerous MRC5. DK-164 demonstrated remarkable selectivity toward cancer cells and more pronounced cytotoxicity against A549. The cytotoxicity of CC-78 toward H1299 was even higher than that of the well-established anticancer drugs cisplatin and tamoxifen, but it did not reveal any noticeable selective effect. DK-164 showed predominantly pro-apoptotic activity in non-small cell lung carcinoma (NSCLC) cells, while CC-78 caused accidental cell death with features characteristic of necrosis. The level of induced autophagy was similar for both substances in cancer cells. DK-164 treatment of A549, H1299, and MRC5 cells for 48 h significantly increased the fluorescence signal of the NFkB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) protein in the nucleus in all three cell lines, while CC-78 did not provoke NFkB translocation in any of the tested cell lines. Both compounds caused a significant transfer of the p53 protein in the nucleus of A549 cells but not in non-cancerous MRC5 cells. In A549, DK-164 generated oxidative stress close to the positive control after 48 h, while CC-78 had a moderate effect on the cellular redox status. In the non-cancerous cells, MRC5, both compounds produced ROS similar to the positive control for the same incubation period. The different results related to the cytotoxic potential of DK-164 and CC-78 associated with the examined cellular mechanisms induced in lung cancer cells might be used to conclude the specific functions of the various functional groups in the ferrocene compounds, which can offer new perspectives for the design of antitumour drugs.
Insights
Two ferrocene derivatives, DK-164 and CC-78, show distinct anticancer effects on lung cancer cells. DK-164 exhibits selectivity and induces apoptosis, while CC-78 is highly cytotoxic but less selective, causing necrosis.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Anticancer drug design increasingly involves combining multiple active subunits to enhance efficacy by targeting diverse cellular pathways.
- Ferrocene derivatives are being explored for their potential therapeutic applications, including anticancer activity.
Purpose of the Study:
- To evaluate the cytotoxic potential and underlying mechanisms of two ferrocene derivatives, DK-164 and CC-78, against non-small cell lung cancer (NSCLC) cell lines.
- To compare the selectivity and cellular effects of DK-164 and CC-78 on cancer versus non-cancerous lung cells.
- To investigate the impact of these compounds on key cellular pathways such as apoptosis, necrosis, autophagy, NFkB, p53, and oxidative stress.
Main Methods:
- Cytotoxicity assays were performed on A549 and H1299 (NSCLC) and MRC5 (non-cancerous) cell lines.
- Cell death mechanisms (apoptosis, necrosis) were assessed.
- Levels of autophagy, nuclear translocation of NFkB (nuclear factor 'kappa-light-chain-enhancer' of activated B-cells) and p53 proteins were measured.
- Oxidative stress (ROS production) was evaluated in treated cells.
Main Results:
- DK-164 displayed significant cytotoxicity and selectivity towards A549 cancer cells, primarily inducing apoptosis.
- CC-78 exhibited potent cytotoxicity against H1299 cells, comparable to cisplatin, but lacked selectivity and induced necrosis.
- Both compounds increased nuclear NFkB in cancer and non-cancerous cells (DK-164 more significantly), and nuclear p53 in A549 cells. DK-164 induced higher oxidative stress in cancer cells, while both induced ROS in non-cancerous cells.
Conclusions:
- DK-164 and CC-78 possess distinct mechanisms of action and selectivity profiles, suggesting their functional groups influence their anticancer properties.
- The differential effects on apoptosis, necrosis, and signaling pathways provide insights for designing novel ferrocene-based anticancer agents.
- Further research into structure-activity relationships can optimize the development of targeted therapies for NSCLC.
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