Antitumor and apoptosis-inducing effects of α-mangostin extracted from the pericarp of the mangosteen fruit (Garcinia mangostana L.) in YD-15 tongue mucoepidermoid carcinoma cells

Abstract

α-mangostin is a dietary xanthone which has been shown to have antioxidant, anti-allergic, antiviral, antibacterial, anti-inflammatory and anticancer effects in various types of human cancer cells. In the present study, we aimed to elucidate the molecular mechanisms responsible for the apoptosis-inducing effects of α-mangostin on YD-15 tongue mucoepidermoid carcinoma cells. The results from MTT assays revealed that cell proliferation significantly decreased in a dose-dependent manner in the cells treated with α-mangostin. DAPI staining illustrated that chromatin condensation in the cells treated with 15 µM α-mangostin was far greater than that in the untreated cells. Flow cytometric analysis indicated that α-mangostin suppressed YD-15 cell viability by inducing apoptosis and promoting cell cycle arrest in the sub-G1 phase. Western blot analysis of various signaling molecules revealed that α-mangostin targeted the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling pathways through the inhibition of ERK1/2 and p38 phosphorylation in a dose-dependent manner. α-mangostin also increased the levels of Bax (pro-apoptotic), cleaved caspase-3, cleaved caspase-9 and cleaved-poly(ADP-ribose) polymerase (PARP), whereas the levels of the anti-apoptotic factors, Bcl-2 and c-myc, decreased in a dose-dependent manner. The anticancer effects of α-mangostin were also investigated in a tumor xenograft mouse model. The α-mangostin-treated nude mice bearing YD-15 tumor xenografts exhibited a significantly reduced tumor volume and tumor weight due to the potent promoting effects of α-mangostin on cancer cell apoptosis, as determined by TUNEL assay. Immunohistochemical analysis revealed that the level of cleaved caspase-3 increased, whereas the Ki-67, p-ERK1/2 and p-p38 levels decreased in the α-mangostin-treated mice. Taken together, the findings of our study indicate that α-mangostin induces the apoptosis of YD-15 tongue carcinoma cells through the ERK1/2 and p38 MAPK signaling pathways.

Synergic Effect of α‐Mangostin on the Cytotoxicity of Cisplatin in a Cervical Cancer Model

“…The present results are similar to those reported in the literature [13, 42] (Figure 5). Although in the coincubation scheme we did not find a significant difference between any of study groups, there is evidence in the literature indicating that α -M induces apoptosis in YD-15 tongue mucoepidermoid carcinoma cells starting at a concentration of 10  μ M [49]. …”

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“…Several studies have reported that α-MG inhibited the MAPK or PI3K/Akt pathway, thereby exerting its inhibition of cell growth and induction of apoptosis in cancer cells [115]. For example, α-MG induced mitochondria-mediated apoptosis of YD-15 tongue carcinoma cells through inhibiting phosphorylation of ERK1/2 and p38 MAPK in a dose-dependent manner [23]. Phosphorylated and total ERK, JNK, and Akt were downregulated in α-MG-treated SW1353 cells, but there were no changes in p38 MAPK [88].…”

“…The proposed mechanism for α-MG-induced apoptosis was that upon α-MG treatment, the extrinsic pathway was activated, procaspase-8 was cleaved to caspase-8, and then further activated the cleavage of Bid to tBid; the tBid then translocated to mitochondria resulting in the activation of the mitochondrial apoptotic pathway [87]. The depletion of mitochondrial membrane potential, decrease in intracellular ATP, downregulation of proapoptotic Bcl-2 and upregulation of antiapoptotic Bax, release of cytochrome c from mitochondria into cytosol, activation of the caspase cascade, and enhancement of PARP cleavage were the main events involved in the mitochondrial apoptotic pathway induced by α-MG [23,88]. However, this was not in agreement with the findings of Matsumoto et al [89] who reported that α-MG directly targeted mitochondria and induced apoptosis as evidenced by the activation of caspases-9 and -3, but not caspase-8.…”

“…Besides, several investigators utilized nude mice models to assess the chemopreventive efficacy of α-MG. The studies were mostly performed in nude mice ectopic xenograft models, where α-MG exhibited significant inhibitory effects against the growth of (i) human colorectal adenocarcinoma HCT116 and HT-29 cells through the induction of apoptosis and inhibition of angiogenesis [19,20], (ii) prostate cancer 22Rv1 cells through arresting cell cycle [21], (iii) human hepatoma SK-Hep-1 cells and tongue mucoepidermoid carcinoma YD-15 cells through the induction of apoptosis [22,23], and (iv) glioblastoma GBM8401 cells through the induction of autophagic death [24]. In addition, for pancreatic cancer, α-MG not only markedly inhibited pancreatic cancer ASPC1 cell-derived ectopic xenograft tumors [25,26], but also PL-45 cell-derived orthotopic xenograft tumors [25], which can better maintain the original biological characteristics of tumor cells and have a relatively higher clinical relevance.…”

The Pivotal Neuroinflammatory, Therapeutic and Neuroprotective Role of Alpha-Mangostin

“…The formed tBid then translocated to mitochondria leading to the stimulation of the mitochondrial apoptotic pathway [2,80]. Studies [2,81,82] have proven that depletion of mitochondrial membrane potential results in reduction in intracellular ATP, downregulation of proapoptotic Bcl-2 and upregulation of antiapoptotic Bax, secretion of cytochrome c from mitochondria into cytosol, stimulation of the caspase cascade, and augmentation of poly (ADP-ribose) polymerase (PARP) cleavage were the main events involved in the mitochondrial apoptotic pathway is triggered by α-MG. Numerous authors [83][84][85] believe that ROS is an interceder during apoptosis signaling.…”