Epoxyazadiradione induced apoptosis/anoikis in triple-negative breast cancer cells, MDA-MB-231, by modulating diverse
Sreerenjini Lakshmi1,2, Jalaja Renjitha2,3, Somappa B Sasidhar2,3
1Biochemistry Section, Agro-Processing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Thiruvananthapuram, Kerala, India.
Abstract:
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of its kind, which accounts for 15-20% of all breast cancers. As this cancer form lacks hormone receptors, targeted chemotherapy remains the best treatment option. Apoptosis and anoikis (detachment-induced cell death) induction by small molecules can prevent TNBC metastasis to a greater extent. Epoxyazadiradione (EAD) is a limonoid from the neem plant with an anticancer property. Here, we demonstrate that EAD induced mitochondria-mediated apoptosis and anoikis in TNBC cells (MDA-MB-231). Apart from this, it promotes antimigration, inhibition of colony formation, downregulation of MMP-9 and fibronectin, induction of G2/M phase arrest with downregulation of cyclin A2/cdk2, interference in cellular metabolism, and inhibition of nuclear factor kappa-B (NF-kB) nuclear translocation. Moreover, a significant reduction is observed in the expression of EGFR on the plasma membrane and nucleus upon treatment with EAD. Among the diverse cellular effects, anoikis induction, metabolic interference, and downregulation of membrane/nuclear EGFR expression by EAD are reported here for the first time. To summarize, EAD targets multiple cellular events to induce growth arrest in TNBC, and hence can be developed into the best antineoplastic agent in the future.
Insights
Epoxyazadiradione (EAD), a neem compound, effectively targets triple-negative breast cancer (TNBC) cells. EAD induces apoptosis, anoikis, and growth arrest, showing potential as a novel antineoplastic agent.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- Inducing apoptosis and anoikis are key strategies to inhibit TNBC metastasis.
- Epoxyazadiradione (EAD), a neem-derived limonoid, exhibits anticancer properties.
Purpose of the Study:
- To investigate the anticancer effects of EAD on TNBC cells.
- To elucidate the mechanisms underlying EAD's action, including apoptosis and anoikis induction.
- To evaluate EAD's impact on cell migration, metabolism, and key signaling pathways.
Main Methods:
- Treatment of MDA-MB-231 TNBC cells with EAD.
- Assessment of apoptosis and anoikis induction.
- Analysis of cell migration, colony formation, cell cycle, and protein expression (MMP-9, fibronectin, cyclin A2/cdk2, NF-kB, EGFR).
- Evaluation of cellular metabolic interference.
Main Results:
- EAD induced mitochondria-mediated apoptosis and anoikis in TNBC cells.
- EAD inhibited cell migration, colony formation, and downregulated MMP-9 and fibronectin.
- EAD caused G2/M phase arrest, interfered with cellular metabolism, and inhibited NF-kB nuclear translocation.
- EAD significantly reduced EGFR expression on plasma membrane and nucleus.
- Anoikis induction, metabolic interference, and EGFR downregulation by EAD are novel findings.
Conclusions:
- EAD exhibits significant anticancer activity against TNBC by targeting multiple cellular pathways.
- EAD effectively induces apoptosis, anoikis, and cell cycle arrest, while inhibiting metastasis-associated factors.
- EAD's novel mechanisms, including metabolic interference and EGFR downregulation, position it as a promising antineoplastic agent for TNBC treatment.
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