α-Mangostin: A Dietary Antioxidant Derived from the Pericarp of Garcinia mangostana L. Inhibits Pancreatic Tumor Growth in Xenograft Mouse Model

Abstract

Aims: Pancreatic cancer (PC) is the most aggressive malignant disease, ranking as the fourth most leading cause of cancer-related death among men and women in the United States. In this study, we provide evidence of chemotherapeutic effects of a-mangostin, a dietary antioxidant isolated from the pericarp of Garcinia mangostana L. against human PC. Results: The chemotherapeutic effect of a-mangostin was determined using four human PC cells (PL-45, PANC1, BxPC3, and ASPC1). a-Mangostin resulted in a significant inhibition of PC cells viability without having any effects on normal human pancreatic duct epithelial cells. a-Mangostin showed a dose-dependent increase of apoptosis in PC cells. Also, a-mangostin inhibited the expression levels of pNF-jB/p65Ser552, pStat3Ser727, and pStat3Tyr705. a-Mangostin inhibited DNA binding activity of nuclear factor kappa B (NF-jB) and signal transducer and activator 3 (Stat3). a-Mangostin inhibited the expression levels of matrix metallopeptidase 9 (MMP9), cyclin D1, and gp130; however, increased expression of tissue inhibitor of metalloproteinase 1 (TIMP1) was observed in PC cells. In addition, i.p. administration of a-mangostin (6 mg/kg body weight, 5 days a week) resulted in a significant inhibition of both primary (PL-45) and secondary (ASPC1) human PC cell-derived orthotopic and ectopic xenograft tumors in athymic nude mice. No sign of toxicity was observed in any of the mice administered with a-mangostin. a-Mangostin treatment inhibited the biomarkers of cell proliferation (Ki-67 and proliferating cell nuclear antigen [PCNA]) in the xenograft tumor tissues. Innovation: We present, for the first time, that dietary antioxidant a-mangostin inhibits the growth of PC cells in vitro and in vivo. Conclusion: These results suggest the potential therapeutic efficacy of a-mangostin against human PC. Antioxid. Redox Signal. 21, 682-699.

TRAIL Mediated Signaling in Pancreatic Cancer

“…Mice xenografted with pancreatic cancer cells displayed decreased proliferation, decreased microvessel density and increased apoptosis upon treatment with Wang et al (2014). α-Mangostin, an antioxidant derived from the Garcinia mangostana L. Expression of pNF-kB/ p65Ser552 was also found to be inhibited in α-Mangostin treated pancreatic cancer cell lines (Hafeez et al, 2014). Wogonin, a naturally occurring flavone was noted to suppress cFLIP in Capan-1 cell line thus restoring TRAIL induced apoptosis.…”

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“…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. Importantly, besides the inhibitory effects on the growth of primary tumors, α-MG has also shown significant antimetastatic effects in animal models.…”

“…This work provides new insights into the molecular basis of α-MGʼs antiproliferative activity outside its role in the p53-p21axis. In other cancer cells, α-MG was reported to arrest the cell cycle at the S phase [78], G0/G1 phase [25,79], or G2/M phase [80]. In addition, α-MGʼs antiproliferative activity might also be ascribed to its direct inhibition of DNA synthesis by diminishing DNA polymerases and topoisomerases.…”

“…TIMPs occur naturally within the extracellular matrix, which inhibit both proand active MMPs and provide a homeostatic environment in the matrix. The anti-invasive potential of α-MG against various pancreatic cancer cell lines was partly ascribed to the upregulation of TIMP1 and subsequent inhibition of MMP9 [25].…”

“…In fact, α-MG not only suppressed the inducible form of NF-κB, but also inhibited constitutively activated NF-κB [78,80]. It interfered with the canonical NF-κB signaling pathway by downregulating the expression of p65/NF-κB, IKKγ (NEMO), and IKKβ in pancreatic cancer cells, which is partly responsible for its capabilities of growth inhibition and apoptosis induction [25]. Besides influencing tumor cell proliferation and survival, NF-κB also promotes invasion, metastasis, and angiogenesis.…”