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Evaluation and Elucidation Studies of Natural Aglycones for Anticancer Potential using Apoptosis-Related Markers: An
Salman Akhtar1,2, M Kalim A Khan1,2, Jamal M Arif3,4
1Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, 226026, India.
Abstract:
Exposure to exogenous and endogenous chemicals and subsequent cellular and molecular changes has been linked to enhanced cell proliferation and restricted apoptosis phenomenon. Though in the past decades numerous anticancer drugs inducing programmed cell death in cancer cells by targeting specific apoptotic markers have reached the market, they have been allied with unwanted side effects, ranging from mild to severe toxicity. With further understanding on the functional mechanism of p53 and MDM2 in apoptosis and in our continuous search for new and potent multi-target anticancer lead compounds, we have carried out molecular docking and inhibition studies of the selected aglycones along with selected anticancer leads, against the specific apoptotic and cell cycle markers using AutoDock Tools 4.0 and other computational softwares. The docking results have been analyzed in terms of binding energies (kcal/mol) and inhibition constant (µM). The study clearly proposes our aglycones [solanidine (Solanid-5-en-3β-ol), solasodine (Solasod-5-en-3β-ol), and tomatidine (5α-Tomatidan-3β-ol)] induce apoptosis by inhibiting the p53-MDM2 complex, p21Waf1/Cip1, and Bcl-2 proteins, which were even found comparable with the anticancer drugs nutlin and/or halofuginone. The work further emphasizes that the individual molecular targets such as BAX and Bcl-2 may result in misleading data at any level; however, ratio of responses to BAX and Bcl-2 shall be considered for better clue about a compound to be pro- or anti-apoptotic.
Insights
New anticancer compounds, solanidine, solasodine, and tomatidine, were found to induce apoptosis by inhibiting key proteins like p53-MDM2. These natural compounds show potential against cancer, comparable to existing drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Chemical exposure can disrupt cellular processes, leading to uncontrolled cell proliferation and reduced apoptosis.
- Current anticancer drugs targeting apoptosis often cause significant side effects due to their toxicity.
- Understanding the p53-MDM2 pathway is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the potential of selected aglycones as multi-target anticancer compounds.
- To evaluate the molecular interactions of these aglycones with apoptotic and cell cycle markers.
- To compare the efficacy of these aglycones with known anticancer drugs.
Main Methods:
- Molecular docking studies using AutoDock Tools 4.0.
- Inhibition assays against specific apoptotic and cell cycle markers.
- Analysis of binding energies (kcal/mol) and inhibition constants (µM).
Main Results:
- Aglycones solanidine, solasodine, and tomatidine demonstrated significant inhibition of the p53-MDM2 complex.
- These compounds also inhibited p21Waf1/Cip1 and Bcl-2 proteins.
- The inhibitory effects were comparable to the anticancer drugs nutlin and halofuginone.
Conclusions:
- The studied aglycones effectively induce apoptosis by targeting key proteins in cancer cells.
- These natural compounds represent promising lead compounds for novel anticancer drug development.
- Evaluating the BAX to Bcl-2 ratio is essential for accurate assessment of a compound's apoptotic potential.
