Dimeric Anthraquinone Rugulosin A Induces Apoptosis in Lung Adenocarcinoma and Targets PI3K/AKT/MAPK Pathways In
Joe Anthony H Manzano1,2,3, Elian Angelo M Abellanosa4, Jose Paolo P Aguilar3
1The Graduate School, University of Santo Tomas, 1015 España, Manila, Philippines.
Abstract:
Cytotoxic anthraquinones are natural products that modulate apoptosis and oncogenic signaling pathways. In this study, three fungal anthraquinones citreorosein (1), skyrin (2), and rugulosin A (3) were investigated for cytotoxic, antiproliferative, and pro-apoptotic effects using in vitro assays. Rugulosin A (3) exhibited cytotoxic activity against six tumorigenic cell lines (IC50 = 0.138-1.475 μM). Although less potent than the nanomolar-range reference drug Epothilone B (IC50 < 0.1 μM), rugulosin A showed submicromolar-to-low micromolar efficacy with notable selectivity toward cancer cells, which is considered significant for an unoptimized natural product scaffold. Its antiproliferative activity against K562 cells (GI50 = 3.69 μM), benchmarked against Imatinib (GI50 = 0.373 μM), also falls within the active range of natural product leads. Caspase-Glo 3/7 and CellEvent assays demonstrated concentration-dependent apoptosis induction by 3 (p < 0.05), supported by Western blot detection of cleaved PARP-1 and caspase-3. Network pharmacology analysis identified ten potential gene targets enriched in oncogenic pathways, with AKT1, PIK3CA, and MAPK14 p38α emerging as putative key regulators. Molecular docking revealed strong binding energies (-10.1, -9.8, and -11.0 kcal/mol), along with a stable molecular dynamics simulations data. These findings highlight rugulosin A (3) as a promising anticancer lead that modulates major apoptosis signaling pathways.
Insights
Rugulosin A, a fungal anthraquinone, shows significant anticancer potential by inducing apoptosis and inhibiting cancer cell growth. This natural product modulates key oncogenic signaling pathways, making it a promising lead for drug development.
Area of Science:
- Natural Product Chemistry
- Pharmacology
- Molecular Biology
Background:
- Cytotoxic anthraquinones are natural products with known roles in modulating apoptosis and oncogenic signaling.
- Fungal-derived compounds represent a rich source of novel therapeutic agents.
Purpose of the Study:
- To investigate the cytotoxic, antiproliferative, and pro-apoptotic effects of three fungal anthraquinones: citreorosein (1), skyrin (2), and rugulosin A (3).
- To identify potential molecular targets and mechanisms of action for rugulosin A.
Main Methods:
- In vitro cytotoxic and antiproliferative assays using various cancer cell lines.
- Apoptosis induction assays (Caspase-Glo 3/7, CellEvent, Western blot for cleaved PARP-1 and caspase-3).
- Network pharmacology analysis and molecular docking simulations.
Main Results:
- Rugulosin A (3) demonstrated significant cytotoxic activity (IC50 = 0.138-1.475 μM) and antiproliferative effects (GI50 = 3.69 μM against K562 cells).
- Rugulosin A induced apoptosis in a concentration-dependent manner, confirmed by caspase activation and PARP-1 cleavage.
- Network pharmacology and molecular docking identified AKT1, PIK3CA, and MAPK14 (p38α) as key potential targets with strong binding affinities.
Conclusions:
- Rugulosin A is a potent anticancer lead compound with selectivity towards cancer cells.
- Its mechanism involves the modulation of critical apoptosis and oncogenic signaling pathways.
- Further development of rugulosin A holds promise for novel cancer therapeutics.
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