α-Mangostin delivered via nanoparticles induced cell death in KRAS mutant pancreatic cancer cells via a synthetic lethal mechanism

α-Mangostin is a xanthonoid extracted from the rind of the fruit (mangosteen (figure 1)) of the tree Garcinia mangostana [1]. Some consider the mangosteen the “Queen of Fruits”. It originates from the islands of Indonesia. The α-Mangostin extract has various biological activities which are currently under investigation, including anti-inflammatory and anti-cancer.

 

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Figure 1: Mangosteen fruit. The edible portion is white whereas the rind from which the α-Mangostin is extracted is redish. Credit: John and Carolina. No changes were made. Creative Commons Attribution-ShareAlike 2.0 Generic (CC BY-SA 2.0).

 

It has recently been shown that in pancreatic cancer mouse models with KRASG12D mutation and in pancreatic cancer cell lines that α-Mangostin delivered via nanoparticles induced apoptosis by an undefined mechanism [2]. It is important to note that nanoparticle delivery results in a high effective concentration of α-Mangostin in the cells. The effects of α-Mangostin on reactive oxygen species (ROS) levels is thought to be concentration dependent- high α-Mangostin concentration increases ROS whereas low concentration can have antioxidant effect. In another study α-Mangostin was found to suppress the activity of the PI3K/Akt pathway and induce apoptosis in pancreatic cancer cell lines [3]. Importantly α-Mangostin had no effect on normal pancreatic cell lines suggesting that it has a synthetic lethal mechanism of action – that is it targeted pathways essential for cancer survival but dispensable in normal cells. KRASG12D mutations are known to make pancreatic cells dependent on antioxidant production for survival or put another way raised ROS levels are lethal [4].

 

In other cancer models α-Mangostin is known to induce apoptosis via endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation. It will be important to investigate this possibility in pancreatic cancer cells. These factors are often associated with immunogenic cell death. In prostate cancer cells α-Mangostin increased apoptosis and ER stress markers including phosphorylated PERK, IRE1, CHOP and spliced XBP-1. Importantly these markers were not induced by α-Mangostin in normal prostate cells [5]. In breast cancer cells α-Mangostin was found to inhibit intracellular fatty acid synthase and induced apoptosis [6]. The inhibition of fatty acid synthase is known to increase reactive oxygen species levels in cancer which is associated with apoptosis [7].

 

The delivery of α-Mangostin to pancreatic cancer cells is an important innovation as it normally has low bioavailability and accumulation in the target organs due to its hydrophobic nature, poor aqueous solubility and stability [2]. The apoptosis induction in other cancer models by α-Mangostin suggests an immunogenic cell death mechanism which will be very important to further investigate especially in pancreatic cancer for which few effective treatments are available.

 

Refs

 

  1. Sobotta, R. and H. P. Ignatow (2006). Process for isolating of alpha-mangostin, US patent US20060014967 A1, Jan 19, 2006.
  2. Verma RK, Yu W, Shrivastava A, Shankar S, Srivastava RK. α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in human, and transgenic (Kras(G12D), and Kras(G12D)/tp53R270H) mice. Sci Rep. 2016 Sep 14;6:32743. doi: 10.1038/srep32743. PubMed PMID: 27624879
  3. Xu Q, Ma J, Lei J, Duan W, Sheng L, Chen X, Hu A, Wang Z, Wu Z, Wu E, Ma Q, Li X. α-Mangostin suppresses the viability and epithelial-mesenchymal transition of pancreatic cancer cells by downregulating the PI3K/Akt pathway. Biomed Res Int. 2014;2014:546353. doi: 10.1155/2014/546353. Epub 2014 Apr 10. PubMed PMID: 24812621.
  4. Kong B, Qia C, Erkan M, Kleeff J, Michalski CW. Overview on how oncogenic Kras promotes pancreatic carcinogenesis by inducing low intracellular ROS levels. Front Physiol. 2013 Sep 12;4:246. doi: 10.3389/fphys.2013.00246. Review. PubMed PMID: 24062691
  5. Li G, Petiwala SM, Nonn L, Johnson JJ. Inhibition of CHOP accentuates the apoptotic effect of α-mangostin from the mangosteen fruit (Garcinia mangostana) in 22Rv1 prostate cancer cells. Biochem Biophys Res Commun. 2014 Oct 10;453(1):75-80. doi: 10.1016/j.bbrc.2014.09.054. Epub 2014 Sep 26. PubMed PMID: 25261723.
  6. Li P, Tian W, Ma X. Alpha-mangostin inhibits intracellular fatty acid synthase and induces apoptosis in breast cancer cells. Mol Cancer. 2014 Jun 3;13:138. doi: 10.1186/1476-4598-13-138. PubMed PMID: 24894151
  7. Zecchin KG, Rossato FA, Raposo HF, Melo DR, Alberici LC, Oliveira HC, Castilho RF, Coletta RD, Vercesi AE, Graner E. Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis. Lab Invest. 2011 Feb;91(2):232-40. doi:10.1038/labinvest.2010.157. Epub 2010 Aug 30. PubMed PMID: 20805790.
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