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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Curcumin analog HO-3867 inhibited STAT3 and induced apoptosis in pancreatic cancer cell lines

 

STATs are transcription factors which are normally present in the cytoplasm and activated by inflammatory signalling associated with epithelial to mesenchymal transition (EMT) which leads to their nuclear import [1]. STAT3 expression is maintained and constitutive activation has been reported in at least 30% of pancreatic cancers [2].

 

Fatty acid synthase (FASN) is a key enzyme involved in lipogenesis and the production of long-chain fatty acids from acetyl-coenzyme A (CoA) and malonyl-CoA which is crucial for rapidly growing cancer cells including pancreatic [3]. The inhibition of fatty acid synthase is known to increase reactive oxygen species (ROS) levels in cancer which is associated with apoptosis [4].

 

Focal Adhesion Kinase (FAK) inhibitors demonstrated in preclinical pancreatic cancer models increased mouse survival time via tumour stasis, reduced collagen deposition and reduced numbers of activated fibroblasts, down-regulated gene expression of fibrosis associated markers, reduced cancer stem-like cell numbers, reduced numbers of immunosuppresive cells within tumours, synergized with gemcitabine treatment, synergized with adoptive T cell transfer to reduce tumour volume and was associated with increased numbers of therapeutic T cell in the tumour and synergised with checkpoint inhibitors under certain circumstances [5].

 

ho-3867
Figure 1: HO-3867 mechanisms of action in cancer cells. HO-3867 down-regulates FASN and FAK protein expression leading to apoptosis and decreased cell migration respectively. HO-3867 also inhibits STAT3 phosphorylation which leads to apoptosis and possibly decreased cell migration.

 

The curcumin analog HO-3867 has recently been shown to inhibit STAT3 and down-regulate fatty acid synthase in pancreatic cancer cells leading to apoptosis via ROS [6]. In addition in ovarian cancer models HO-3867 down-regulates FAK [7]. The potential to inhibit STAT3, FASN and FAK with a single agent is very promising and warrants further investigation as a potential therapeutic for pancreatic cancer (Figure 1).

 
Refs

 

  1. Kaplan, Mark H. ‘STAT Signaling in Inflammation’. JAK-STAT 2, no. 1 (January 2013): e24198. doi:10.4161/jkst.24198.
  2. Corcoran, R. B., G. Contino, V. Deshpande, A. Tzatsos, C. Conrad, C. H. Benes, D. E. Levy, J. Settleman, J. A. Engelman, and N. Bardeesy. ‘STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis’. Cancer Research 71, no. 14 (15 July 2011): 5020–29. doi:10.1158/0008-5472.CAN-11-0908.
  3. Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010 Apr;6(4):551-62. Doi: 10.2217/fon.10.11. Review. PubMed PMID: 20373869.
  4. 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.
  5. Jiang, Hong, Samarth Hegde, Brett L Knolhoff, Yu Zhu, John M Herndon, Melissa A Meyer, Timothy M Nywening, et al. ‘Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy’. Nature Medicine, 4 July 2016. doi:10.1038/nm.4123. PMID: 27376576.
  6. Hu Y, Zhao C, Zheng H, Lu K, Shi D, Liu Z, Dai X, Zhang Y, Zhang X, Hu W, Liang G. A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells. Anticancer Drugs. 2017 Jan 6. doi: 10.1097/CAD.0000000000000470. PubMed PMID: 28067673.
  7. Selvendiran K, Ahmed S, Dayton A, Ravi Y, Kuppusamy ML, Bratasz A, Rivera BK, Kálai T, Hideg K, Kuppusamy P. HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase. Mol Cancer Res. 2010 Sep;8(9):1188-97. doi: 10.1158/1541-7786.MCR-10-0201. PubMed PMID: 20713491.

 

 

Immune stimulation with PEGylated human IL-10 (AM0010) in patients with pancreatic and colorectal cancer

 

AM0010 is being developed by ARMO BioSciences.

PEGylation of IL-10 allows for an extended half life in the body.

IL-10 is known to induce activation of STAT3 in CD8+ T cells which leads to increased survival, proliferation and cytotoxicity towards cancer. In preclinical studies, PEGylated IL-10 induced CD8+ T cell mediated tumor rejection and synergized with cytotoxic chemotherapies [1].

AM0010 is currently undergoing a phase I clinical trial for patients with advanced solid tumors including pancreatic and colon cancer [2]. Preliminary data suggested that AM0010 enhanced immune stimulation in these “immune resistant” cancers [3].

It is important to note that the mechanism of action of AM0010 relies upon the presence of CD8+ T cells within the tumor. Agents that promote the presence of of these cells are likely to be synergistic with AM0010.

 

Refs

  1. Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, Blaisdell S, Basham B, Dai J, Grein J, Sheppard C, Hong K, Cutler C, Turner S, LaFace D, Kleinschek M, Judo M, Ayanoglu G, Langowski J, Gu D, Paporello B, Murphy E, Sriram V, Naravula  S, Desai B, Medicherla S, Seghezzi W, McClanahan T, Cannon-Carlson S, Beebe AM, Oft M. IL-10 elicits IFNγ-dependent tumor immune surveillance. Cancer Cell. 2011  Dec 13;20(6):781-96. doi: 10.1016/j.ccr.2011.11.003. PubMed PMID: 22172723.
  2. A Phase 1 Study of AM0010 in Patients With Advanced Solid Tumors. NCT02009449.
  3. J Clin Oncol 34, 2016 (suppl; abstr 3082). Poster.