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].


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.




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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].


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).



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  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.



  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.