Alpha-mangostin induces apoptosis through activation of reactive oxygen species and ASK1/p38 signaling pathway in cervical cancer cells

Abstract

Alpha-mangostin, a natural xanthonoid, has been reported to possess the anti-cancer property in various types of human cancer. However, its effects and mechanism of α-mangostin in cervical cancer remain unclear. We found that α-mangostin effectively inhibited cell viability, resulted in loss of mitochondrial membrane potential (MMP), release of cytochrome C, increase of Bax, decrease of Bcl-2, and activation of caspase-9/caspase-3 cascade in cervical cancer cells. Alpha-mangostin elevated the contents of reactive oxygen species (ROS) to activate p38. Disrupting ASK1/p38 signaling pathway by a specific inhibitor of p38, or by the siRNAs against ASK1, MKK3/6, or p38, significantly abolished α-mangostin-induced cell death and apoptotic responses. Moreover, α-mangostin also repressed tumor growth in accordance with increased levels of p-ASK1, p-p38, cleaved-PARP and cleaved-caspase-3 in the tumor mass from the mouse xenograft model of cervical cancer. In the current study, we provided first evidence to demonstrate that dietary antioxidant α-mangostin could inhibit the tumor growth of cervical cancer cells through enhancing ROS amounts to activate ASK1/p38 signaling pathway and damage the integrity of mitochondria and thereby induction of apoptosis in cervical cancer cells.

α‐Mangostin attenuates stemness and enhances cisplatin‐induced cell death in cervical cancer stem‐like cells through induction of mitochondrial‐mediated apoptosis

“…Therefore, new therapeutic compounds with lower toxicity have been found to be an urgent need for cancer treatment. Our previous study demonstrates that α‐mangostin can activate reactive oxygen species signaling and induce apoptosis of HeLa cell (Lee et al, 2017), suggesting that α‐mangostin has potential anticancer activity against cervical cancer cells. Similarly, α‐mangostin has been reported to show a synergistic effect on cisplatin‐induced cytotoxicity on the HeLa cell in vitro and in vivo (Perez‐Rojas et al, 2016).…”

“…Therefore, new therapeutic compounds with lower toxicity have been found to be an urgent need for cancer treatment. Our previous study demonstrates that α-mangostin can activate reactive oxygen species signaling and induce apoptosis of HeLa cell (Lee et al, 2017),…”

“…Our previous study showed that α‐mangostin clearly induced apoptosis of cervical cancer cells (Lee et al, 2017). In the present study, we further investigated the anticancer activity of α‐mangostin on CSC‐like cervical cancer cells.…”

“…Among the natural compounds, xanthones have many reports demonstrating their anticancer activity against different types of malignancies (Alves et al, 2019; Gao et al, 2019; Shan et al, 2011). It has been reported that natural xanthones mangostins isolated from mangosteen have potent anticancer activity against several cancer cells such as leukemia HL60 (Matsumoto et al, 2003) and cervical cancer cell HeLa (Lee et al, 2017). However, whether α‐mangostin possesses the anticancer activity against CSC‐like cervical cancer cells remains unclear.…”

<p>Nanoparticle Drug Delivery Systems for α-Mangostin</p>

“…[1][2][3][4][5] The anticancer activity indicates that α-mangostin might serve as a potent anticancer agent in lung, stomach, colon, cervical, pancreatic, prostate, mammary gland, chondrosarcoma, renal, skin, tongue mucoepidermoid and breast cancers. [6][7][8][9][10][11][12][13][14][15][16][17][18] However, αmangostin has low solubility in water (2.03 x 10 −4 mg/L at 25ºC), and many efforts have been made to improve it: structure modification, co-solvation, solid dispersion, emulsion, complexation and nanoparticle drug delivery systems. [19][20][21] Additionally, αmangostin and other cytotoxic drugs generally have limitations that influence their effectiveness, including a first fast metabolism reaction, an efflux reaction induced by transporter intercellular, fast drug release and a non-specific target site.…”