Exploring the antineoplastic potential of α-mangostin in breast cancer

Abstract

Among women, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related mortality globally. Despite improvements in early detection and diagnosis, some risk factors have been on the rise, including the decline in birth rate, the use of oral contraceptives, and the escalation in alcohol consumption and obesity. Thus, there is an imperative urgent need to expand accessible prevention and treatment options for breast cancer. Regarding these tumors, several natural compounds have shown efficacy in slowing or preventing their progression, offering a promising therapeutic alternative. Among these, α-mangostin, a xanthone derived from mangosteen, has demonstrated promising antitumor effects against different malignancies, particularly breast cancer. The mechanisms involved in α-mangostin´s therapeutic effects include downregulation of oncogenic ion channels, modulation of cell cycle progression, suppression of oncogene expression, and interference with steroid and growth factor receptors signaling. This review thoroughly explores these mechanisms, as well as updates information on α-mangostin chemical structure and its potential as a coadjuvant to conventional breast cancer therapies. Furthermore, we provide scientifically supported insights for the development of clinically applicable α-mangostin-based treatments, highlighting the robust body of evidence supporting its cancer-fighting properties, despite the absence of clinical studies to date.

Keywords: Antineoplastic effects; Breast cancer; Garcinia mangostana; Xanthone; α-Mangostin.

Fig. 1

Mangosteen fruit. The mangosteen fruit has a thick outer rind, known as the pericarp (rind or peel), which measures approximately 1.0 cm in thickness and encases the inner white pulp. The pulp, about 4.5 cm in diameter, consists of 4 to 7 soft, juicy arils with a sweet yet slightly acidic flavor. The entire fruit has an average diameter of 6.5 cm

Fig. 2

Chemical structure of the major prenylated xanthones from mangosteen pericarp. The xanthone nucleus is an aromatic oxygenated heterocyclic molecule with a planar, symmetric, and tricyclic structure, comprising two aromatics rings: A-ring (carbons 1–4) and B-ring (carbons 5–8), connected by the C ring (γ-pyrone ring, carbon 9). The prenylated xanthones feature prenyl groups and vary in the number and position of these groups, as well as the hydroxyl and methoxy groups attached to the xanthone nucleus. These variations are believed to significantly influence the biological activities of the xanthones. The structures were created in ChemDraw version 20.0.0.41 (1998–2000 PerkinElmer informatics, Inc)

Fig. 3

Antiproliferative mechanisms of α-mangostin. α-Mangostin (AM) exhibits diverse mechanisms to inhibit breast cancer cell proliferation, including: (1) Hormonal receptor modulation: AM reduces ERα expression and phosphorylation, increases ERβ levels, and inhibits estrogen-dependent gene expression. Docking studies indicate strong interactions with ERs, and derivatives of AM act as potential ER antagonists. (2) Blockade of growth factor receptor signaling: AM inhibits HER-2 phosphorylation and EGFR, and VEGFR binding, downregulating key oncogenic pathways (RAS/RAF1/MEK/ERK and PI3K/AKT). (3) Histamine H₁ receptor (H₁R) inhibition: AM blocks H₁R, linked to tumor growth, and reduces breast cancer histamine levels. (4) Enzyme inhibition: AM targets aromatase, topoisomerases, DNA polymerases, Lysine-Specific Demethylase 1 (LSD1), and fatty acid synthase (FAS), disrupting proliferation, DNA processes, and lipid synthesis. (5) Ion channel modulation: AM inhibits oncogenic potassium channels (KCNH1, Kv1.3, KCa3.1), calcium transport (ORAI1, Ca²⁺ ATPase), impacting cell signaling and viability. (6) Cell cycle modulation: AM induces G1-phase arrest and downregulates cyclin-CDK complexes, preventing uncontrolled cell division. Figure created using BioRender.com

Fig. 4

Antiapoptotic mechanisms of α-mangostin. The xanthone α-mangostin (AM) triggers apoptosis via the extrinsic pathway, initiated by ligand-receptor interactions leading to caspase-8 activation, and the intrinsic pathway, which involves mitochondrial membrane depolarization, cytochrome c release, and caspase-9 activation. Both pathways converge on the activation of caspase-3, cleavage of PARP, and execution of apoptosis. AM regulates BCL-2 family protein, downregulating BCL-2, BID, MCL-1, BCL-XL, and BAD, and upregulating BAX. Also, AM affects apoptosis through an independent caspase pathway, including apoptosis-inducing factor (AIF). Additionally, AM downregulates AKT and ERK1/2 signaling while enhancing JNK1/2 and p38 phosphorylation, favoring apoptotic cell death. AM-induced apoptosis is mediated by the Modulator of Apoptosis 1 (MOAP-1), which interacts with activated BAX while downregulating BCL-XL. AM also increases p53 expression, targets mitochondrial respiratory chain complex II, inhibits oxidative mitochondrial respiration (OXPHOS), and increases ROS production. Figure created using BioRender.com

Fig. 5

Mechanisms by which α-mangostin inhibits adhesion, invasion and metastasis. The α-mangostin (AM) downregulates mesenchymal markers (N-cadherin, vimentin, Snail) while upregulating the epithelial marker E-cadherin, counteracting EMT progression. AM suppresses TPA-induced expression and activity of matrix metalloproteinases (MMP-2 and MMP-9) by inhibiting ERK phosphorylation and reducing c-Fos, c-Jun DNA binding activity and reducing TNF-α-induced NF-κB and AP-1 nuclear translocation. AM increases IκK expression, blocking IκBα phosphorylation and further decreasing MMP expression. AM also inhibits STAT3 activation, reducing EMT-associated gene expression, and impairs CXCR4 signaling, inhibiting migration and invasion. Disrupts FAK activation by inhibiting phosphorylation. Additionally, AM downregulates FAS, which may attenuate FAK activity. Figure created using BioRender.com

Fig. 6

Antiangiogenic effects of α-mangostin in endothelial cells. α-Mangostin (AM) exerts its antiangiogenic effects through multiple mechanisms. AM reduces reactive oxygen species (ROS) production in hypoxic endothelial cells and decreases VEGF protein expression. It also inhibits VEGFR-2 phosphorylation at tyrosine residue Y1175, thereby disrupting key downstream signaling pathways involved in angiogenesis. These include the inhibition of AKT phosphorylation, inhibiting endothelial cell proliferation, and tube formation. AM reduces vessel permeability by reducing endothelial nitric oxide synthase (eNOS) activity. Also, VEGFR-2 inhibition prevents MAPK/ERK1/2 activation, reducing endothelial cell proliferation. Additionally, AM inhibits angiogenic sprouting, endothelial cell migration, and microvessel density. These effects have been demonstrated in both in vitro models (HUVECs, RECs, and HUAECs) and in vivo murine xenograft models. Figure created using BioRender.com