Paeonol an anti-cancer agent with potential for synergy with immunotherapeutics

 

Paeonol, 1-(2-Hydroxy-4-methoxyphenyl) ethanone (figure 1) is a phenolic compound found in peonies such as Paeonia suffruticosa (moutan cortex), in Arisaema erubescens, and in Dioscorea japonica. It is a component of some traditional Chinese medicines [1].

 

paeonol
Figure 1: Paeonol, 1-(2-Hydroxy-4-methoxyphenyl) ethanone.

 

Paeonol has been demonstrated to induce apoptosis in a wide range of cancers including ovarian, gastric, colon, esophageal, hepatocellular, breast, melanoma, prostate and lung [2, 3, 4, 5, 6, 7, 8, 9, 10].

 

Paeonol appears to have anti-inflammatory and possibly anti-fibrotic capacity. In CW-2 large intestine carcinoma cell line paeonol inhibited tumor necrosis factor alpha (TNFα)-induced transcriptional activity of NF-κB and interferon gamma (IFNγ) induction of STAT1 [11]. It may also have an inhibitory effect on STAT3 [3]. In colon cancer cells paeonol was found to increase RUNX3 expression levels. RUNX3 has a complex role in the fibrosis promoting process of epithelial to mesenchymal transition (EMT), however at least in certain contexts RUNX3 prevents EMT [12, 13]. Drug resistance and immunosuppression are associated with EMT.

 

Importantly paeonol was found to alleviate drug resistance. It enhanced the efficacy of cisplatin [14], doxorubicin [15], and paclitaxel [16]. These effects may be mediated through inhibition of the Akt pathway [17] in addition to any anti-fibrotic mechanism of action.

 

Paeonol can potentially “heat up” the immunosuppressive microenvironment of immunotherapy resistant tumours as it has been found to reduce the expression of Cyclooxygenase-2 (COX-2) and therefore reduce the levels of its metabolite prostaglandin E2 (PGE2) [18]. PGE2 is known to promote the presence of active myeloid-derived suppressor cells (MDSC) within the tumour microenvironment which inhibit CD4+ and CD8+ T cells [19]. Paeonol may therefore be synergistic with the new class of cancer immunotherapeutics.

 

Refs

 

  1. Deng C, Yao N, Wang B, Zhang X. Development of microwave-assisted extraction followed by headspace single-drop microextraction for fast determination of paeonol in traditional Chinese medicines. J Chromatogr A. 2006 Jan 20;1103(1):15-21. PubMed PMID: 16309693.
  2. Xu Y, Zhu JY, Lei ZM, Wan LJ, Zhu XW, Ye F, Tong YY. Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3. J Physiol Biochem. 2016 Nov 10. PubMed PMID: 27834040.
  3. Zhang L, Tao L, Shi T, Zhang F, Sheng X, Cao Y, Zheng S, Wang A, Qian W, Jiang L, Lu Y. Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-κB and STAT3 pathways. IUBMB Life. 2015 Oct;67(10):778-88. doi: 10.1002/iub.1435. PubMed PMID: 26452780.
  4. Ou Y, Li Q, Wang J, Li K, Zhou S. Antitumor and Apoptosis Induction Effects of Paeonol on Mice Bearing EMT6 Breast Carcinoma. Biomol Ther (Seoul). 2014 Jul;22(4):341-6. doi: 10.4062/biomolther.2013.106. PubMed PMID: 25143814.
  5. Lei Y, Li HX, Jin WS, Peng WR, Zhang CJ, Bu LJ, Du YY, Ma T, Sun GP. The radiosensitizing effect of Paeonol on lung adenocarcinoma by augmentation of radiation-induced apoptosis and inhibition of the PI3K/Akt pathway. Int J Radiat Biol. 2013 Dec;89(12):1079-86. doi: 10.3109/09553002.2013.825058. PubMed PMID: 23875954.
  6. Yin J, Wu N, Zeng F, Cheng C, Kang K, Yang H. Paeonol induces apoptosis in human ovarian cancer cells. Acta Histochem. 2013 Oct;115(8):835-9. Doi: 10.1016/j.acthis.2013.04.004. PubMed PMID: 23768958.
  7. Li N, Fan LL, Sun GP, Wan XA, Wang ZG, Wu Q, Wang H. Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol. 2010 Sep 21;16(35):4483-90. PubMed PMID: 20845518.
  8. Xing G, Zhang Z, Liu J, Hu H, Sugiura N. Antitumor effect of extracts from moutan cortex on DLD-1 human colon cancer cells in vitro. Mol Med Rep. 2010 Jan-Feb;3(1):57-61. doi: 10.3892/mmr_00000218. PubMed PMID: 21472200.
  9. Sun GP, Wan X, Xu SP, Wang H, Liu SH, Wang ZG. Antiproliferation and apoptosis induction of paeonol in human esophageal cancer cell lines. Dis Esophagus. 2008;21(8):723-9. doi: 10.1111/j.1442-2050.2008.00840.x. PubMed PMID: 18522637.
  10. Chunhu Z, Suiyu H, Meiqun C, Guilin X, Yunhui L. Antiproliferative and apoptotic effects of paeonol on human hepatocellular carcinoma cells. Anticancer Drugs. 2008 Apr;19(4):401-9. doi: 10.1097/CAD.0b013e3282f7f4eb. PubMed PMID: 18454050.
  11. Ishiguro K, Ando T, Maeda O, Hasegawa M, Kadomatsu K, Ohmiya N, Niwa Y, Xavier R, Goto H. Paeonol attenuates TNBS-induced colitis by inhibiting NF-kappaB and STAT1 transactivation. Toxicol Appl Pharmacol. 2006 Nov 15;217(1):35-42. PubMed PMID: 16928387.
  12. Whittle MC, Izeradjene K, Rani PG, Feng L, Carlson MA, DelGiorno KE, Wood LD, Goggins M, Hruban RH, Chang AE, Calses P, Thorsen SM, Hingorani SR. RUNX3 Controls a Metastatic Switch in Pancreatic Ductal Adenocarcinoma. Cell. 2015 Jun 4;161(6):1345-60. doi: 10.1016/j.cell.2015.04.048. PubMed PMID: 26004068.
  13. Voon DC, Wang H, Koo JK, Nguyen TA, Hor YT, Chu YS, Ito K, Fukamachi H, Chan SL, Thiery JP, Ito Y. Runx3 protects gastric epithelial cells against epithelial-mesenchymal transition-induced cellular plasticity and tumorigenicity. Stem Cells. 2012 Oct;30(10):2088-99. doi: 10.1002/stem.1183. PubMed PMID: 22899304.
  14. Xu SP, Sun GP, Shen YX, Peng WR, Wang H, Wei W. Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines. Acta Pharmacol Sin. 2007 Jun;28(6):869-78. PubMed PMID: 17506946.
  15. Fan L, Song B, Sun G, Ma T, Zhong F, Wei W. Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells. PLoS One. 2013 May 3;8(5):e62627. Doi: 10.1371/journal.pone.0062627. PubMed PMID: 23658755.
  16. Cai J, Chen S, Zhang W, Hu S, Lu J, Xing J, Dong Y. Paeonol reverses paclitaxel resistance in human breast cancer cells by regulating the expression of transgelin 2. Phytomedicine. 2014 Jun 15;21(7):984-91. doi: 10.1016/j.phymed.2014.02.012. PubMed PMID: 24680370.
  17. Zhang W, Cai J, Chen S, Zheng X, Hu S, Dong W, Lu J, Xing J, Dong Y. Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway. Mol Med Rep. 2015 Jul;12(1):1506-14. doi: 10.3892/mmr.2015.3468. PubMed PMID: 25760096.
  18. Li M, Tan SY, Wang XF. Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE₂ synthesis and COX-2 expression. Oncol Rep. 2014 Dec;32(6):2845-53. doi: 10.3892/or.2014.3543. PubMed PMID: 25322760.
  19. Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res. 2007 May 1;67(9):4507-13. PubMed PMID: 17483367.

 

 

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