Exploring apoptotic induction of malabaricone A in triple-negative breast cancer cells: an acylphenol phyto-entity isolated from the fruit rind of Myristica malabarica Lam.†

Abstract

Myristica malabarica Lam., commonly known as Malabar nutmeg or false nutmeg, is used in traditional medicine and as a spice. Our exploration focuses on malabaricones, a distinct group of secondary metabolites isolated from the fruit rind of M. malabarica. We investigated the selective cytotoxicity of malabaricones against the triple-negative breast cancer (TNBC) cell line. In particular, malabaricone A (Mal-A) displays heightened toxicity towards TNBC cells (MDA-MB-231), with an IC₅₀ of 8.81 ± 0.03 μM. In vitro fluorimetric assays confirmed the apoptotic capability of Mal-A and its capacity to induce nuclear fragmentation. Additionally, ultrasensitive surface-enhanced Raman spectroscopy confirms DNA fragmentation during cellular apoptosis. Cell cycle analysis indicates arrest during the sub-G₀ phase by downregulating key regulatory proteins involved in cell cycle progression. Increased expression levels of caspase 3, 9, and 8 suggest involvement of both extrinsic and intrinsic apoptotic pathways. Finally, assessment of protein expression patterns within apoptotic pathways reveals upregulation of key apoptotic proteins like Fas/FasL, TNF/TNFR1, and p53, coupled with downregulation of several inhibitors of apoptosis proteins such as XIAP, cIAP-2, and Livin. These findings are further verified with in silico molecular docking. Mal-A reveals a strong affinity towards apoptotic proteins, including TNF, Fas, HTRA, Smac, and XIAP, with docking scores ranging from −5.1 to −7.2 kcal mol⁻¹. Subsequently, molecular dynamics simulation confirms the binding stability. This conclusive in vitro evaluation validates Mal-A as a potent phyto-entity against TNBC. To the best of our knowledge, this study represents the first comprehensive anticancer evaluation of Mal-A in TNBC cells.