# Xanthone Derivatives in the Fight against Glioblastoma and Other Cancers
## 2 Antineoplastic Activity of Xanthone Derivatives  
### Mangostin Isomers and Derivatives  
#### Apoptosis Phenomenon  
_Garcinia mangostana_ pericarp (Mangosteen) has proved active against breast cancer [38]. _Garcinia mangostana_ extract contains in its composition: mainly \(\alpha\)-Mangostin (80-90%), \(\beta\)Mangostin, \(\gamma\)-Mangostin,methoxy-\(\beta\)-Mangostin, Garcinone E, 1,3,6,7-Tetrahydroxyaxantho ne, Mangostenone E, 11-Hydroxy-1-isomangostin, and four newly discovered xanthone analogues: Garcinoxanthones S-V [39; 40; 41; 42]. The activity was observed in the **MCF-7** breast cancer cell line, which is an in vitro model of overexpressed ER-\(\alpha\) cells. The Mangosteen pericarp extract exhibits strong cytotoxic activity on **MCF-7** cells with **IC\({}_{\text{50}}\)** of **45 \(\upmu\)g/mL** (MTT test) and apoptosis induction was observed; although, Mangosteen pericarp extract did not suppress the ER-\(\alpha\) either in the nucleus or cytoplasm. The conclusion is that its anticancer activity might be mediated by other genes involved in the ER-\(\alpha\) signaling pathway in breast cancer cells. The Mangosteen cytotoxic and proapoptotic activity was lower compared to that of Tamoxifen [38]. The pericarp extract contains four preralylated xanthone derivatives: \(\alpha\)-Mangostin, \(\beta\)-Mangostin, \(\gamma\)-Mangostin, and methoxy-\(\beta\)-Mangostin (Figure 2), which have been evaluated in various human cancer cells. The first three derivatives are cytotoxic in the **human leukemia cell line HL60** (tested concentrations from **5 to 20 \(\upmu\)M**), \(\alpha\)-Mangostin showed the most pronounced effect in concentrations of 10 \(\upmu\)M and 20 \(\upmu\)M. Methylation of R\({}_{2}\) (4, Figure 2, \(\beta\)-Mangostin-OMe) significantly reduced the activity. The antiproliferative activity of \(\alpha\)-Mangostin could result from the apoptotic process. \(\alpha\)-Mangostin induces caspase-3-dependent apoptosis in HL60 cells, and may therefore mediate the mitochondrial pathway during apoptosis. One to two in after the application of the compound, the parameters of mitochondrial dysfunction, which include swelling, loss of membrane potential (DFm), a decrease in intracellular ATP, ROS accumulation, and cytochrome c/AF release were observed. On the other hand, \(\alpha\)-Mangostin-treatment did not affect the expression of the Bcl-2 family proteins. Activation of MAP kinases was not observed. This can indicate that \(\alpha\)-Mangostin preferentially targets mitochondria in the early phase, resulting in the indication of apoptosis in HL60 cells [43]. Even more pronounced growth suppression has been observed on human **colon cancer DLD-1 cells** for \(\alpha\)-Mangostin (**IC\({}_{\text{50}}\)** = 7.5 \(\upmu\)M, cytotoxicity at **20 \(\upmu\)M, trypan blue assay) [44]. \(\alpha\)-Mangostin induces apoptosis through the down-regulation of signaling involving MAP kinases and the serine/threonine kinase Akt. It also exhibits synergistic effects with the anti-cancer drug 5-fluorouracil. The synergistic growth suppression in **DLD-1** cells by the combined treatment with \(\alpha\)-Mangostin and 5-fluorouracil cell both at **2.5 \(\upmu\)M**, resulted in more pronounced growth inhibition than with the treatment with 5 \(\upmu\)M of \(\alpha\)-mangostin or 5 \(\upmu\)M 5-fluorouracil alone. These findings indicate unique mechanisms of \(\alpha\)-Mangostin-induced apoptosis and its action as an effective chemosensitiver. Mangostin alone exhibited a cytotoxic effect at 20 \(\upmu\)M mainly due to caspase-independent apoptosis [44]. \(\alpha\)-Mangostin properties were also tested in vitro against three human cell lines: **squamous carcinoma SCC-15** (human tongue, Squamous Cell Carcinoma) and **giholastoma multiforme U-118 MG** (human glioblastoma astrocytoma cells) and was compared to normal **skin fibroblasts BJ**[45].