Xanthones from mangosteen extracts as natural chemopreventive agents: potential anticancer drugs

Abstract

Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including antioxidant, anti- tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent.

Fig. 1

Chemical structure of major xanthones isolated from the pericarp of mangosteen (Garcinia mangostana Linn., GML).

Fig. 2

Biochemical mechanisms responsible for chemopreventive and chemotherapeutic potential of xanthones.

Fig. 3

Anti-carcinogenesis effects: xanthones modulate carcinogen detoxification mechanism. Many pollutants such as cigarette smoke, industrial emissions, and gasoline vapors can be converted to active carcinogens and produce excessive amounts of reactive oxygen intermediates (ROI). These mediators could cause DNA damage, genomic instability, and carcinogenesis. Xanthones can prevent the malignant conversion of precancerous cells by impacting phase I and phase II enzymes activities and inhibiting ROI generation.

Fig. 4

Schematic diagram shows the possible effect of xanthones on the apoptosis pathways. Xanthones induce apoptosis occurrence, preferentially activate the mitochondrial pathway, support intracellular ATP decrease, cytochrome c/AIF release, caspase-9 and caspase-3 activation, endonuclease-G release. Furthermore, xanthones also influence cancer cells apoptosis via miR-143/ERK5/c-Myc pathway, NO inhibition, cell-cycle arrest, sarco-endoplasmic reticulum Ca²⁺-ATPase inhibition, and intracellular ROS accumulation.

Fig. 5

An overview: how xanthones induce cell-cycle arrest. Xanthones block the cell cycle by activation or inhibition of cyclins, cdks, inhibitor of cdks, transcription factors or oncoproteins in cancer cells.

Fig. 6

Simplified model showed potential contributions of xanthones to cancer invasion and metastasis. Some external stimulator (PMA, TPA) induce the cell-matrix adhesion, invasion, and migration of cancer cells by upregulating MAPK kinases such as JNK or ERK1/2. Xanthones diminish the above induced effect, prevent NF-κB and AP-1 binding activity, and block their DNA binding site. Consequently, the expression of downstream genes (MMP-2, MMP-9, and u-PA) is downregulated.