Table 3.
Therapeutic agents that have been evaluated in experimental/pre-clinical studies targeting pancreatic stellate cells and cancer stroma in pancreatic ductal adenocarcinoma
| Ref | Agent | Class/type of agent | In vivo/in vitro (study) model | Outcome of the study |
| Feldmann et al[219] 2007 | Cyclopamine | Steroidal alkaloid | Orthotopic xenograft model | Inhibited cancer cell invasion and metastasis by suppressing hedgehog |
| Diep et al[220] 2011 | Erlotinib RDEA119 and AZD6244 | EGFR tyrosine Kinase and MAP kinase inhibitors | In vitro: Pancreatic cancer cell lines In vivo: BxPC-3 and MIA PaCa-2 mice xenograft model | Inhibited cancer cell proliferation, EGF receptor signaling and induced apoptosis |
| Suppressed tumour growth | ||||
| Froeling et al[221] 2011 | ATRA, 9-cis-RA and 13-cis-RA | Metabolites of vitamin A | In vivo: LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice In vitro: AsPc1 and Capan1 pancreatic cancer cell lines, PS1 and other PSC cell lines | Retinoic acid induced PSC quiescence and decreased migration |
| Decreased and induced proliferation and apoptosis of cancer cells | ||||
| Chauhan et al[222] 2013 | Losartan | Angiotensin inhibitor | Orthotopic mice model | Reduced stromal collagen production, expression of TGF-β1, CCN2 and ET-1 |
| Improved drug and oxygen delivery to tumour | ||||
| Sun et al[223] 2013 | Curcumin | Phenolic compound | TGF-β1 stimulated PANC-1 cell line | Inhibited proliferation and promoted apoptosis |
| Cancer cell invasion and migration was decreased | ||||
| Edderkaoui et al[224] 2013 | Ellagic acid Embelin | Polyphenolic and benzoquinone phytochemical | Pancreatic cancer cells and PSCs | Induced apoptosis and inhibited proliferation |
| NF-κB activity was decreased | ||||
| Macha et al[225] 2013 | Guggulsterone | Plant polyphenol | CD18/HPAF and Capan1 cell clones | Inhibited growth and colony formation |
| Induced apoptosis and arrested cell cycle | ||||
| Decreased motility and invasion | ||||
| Kozono et al[226] 2013 | Pirfenidone | Pyridone compound | In vivo: Orthotopic tumour mice Model In vitro: PSCs isolated from pancreatic tissue | In vivo: Reduced tumour growth, PSC proliferation and the deposition of collagen type I and periostin in tumours was decreased |
| In vitro: Proliferation, invasiveness and migration of PSCs was inhibited | ||||
| Guan et al[227] 2014 | Retinoic acid | Vitamin A derivative | Panc-1 and Aspc-1 cell lines Cancer associated fibroblasts | Reduced α-SMA, FAP and IL-6 expression |
| Inhibited cancer cell migration and EMT | ||||
| Gonzalez-Villasana et al[228] 2014 | Bisphosphonates and nab-paclitaxel | Monocyte-macrophage lineage inhibitors | In vitro: Human PSCs and cancer cell line In vivo: Orthotopic mice model | In vitro: Inhibited PSC activation, proliferation MCP-1 release and collagen 1 expression and induced apoptosis |
| In vivo: Reduced tumour size, fibrosis, proliferation and increased apoptosis | ||||
| Pomianowska et al[229] 2014 | Prostaglandin E2 (PGE2) | Lipid compound | Human PSCs isolated from resected pancreatic tumour tissue | IL-1β and EGF induced COX-2 expression, TGF-β induced collagen synthesis and PDGF induced PSC proliferation was inhibited |
| Gong et al[230] 2014 | Nexrutine | Phytoceutical with COX-2 Inhibitor activity | In vitro: pancreatic cancer cell lines In vivo: BK5-COX-2 transgenic mice | In vitro: promoted cancer cell apoptosis and reduced their growth |
| Suppressed COX-2 expression | ||||
| In vivo: NF-κB and Stat3 activity and fibrosis was decreased | ||||
| Yan et al[231] 2014 | Crizotinib | c-MET/HGF receptor and ALK tyrosine kinases inhibitor | In vitro: Human pancreatic cancer cell lines AsPC-1, PANC-1, MIA PaCa-2 and Capan-1 In vivo: Mouse xenograft model | In vitro: Growth and proliferation was inhibited |
| Induced apoptosis | ||||
| Inhibited ALK activity | ||||
| In vivo: Inhibited angiogenesis, tumour growth and ALK activity | ||||
| Zhang et al[232] 2014 | 5-Azacytidine | Cytidine analogue | Bxpc-3 cancer cell line | Inhibited cancer cell proliferation by suppressing Wnt/β-catenin signaling |
| Wang et al[233] 2014 | miR-216a | microRNA | In vitro: Capan-2 and PANC-1 pancreatic cancer cell lines In vivo: BALB/c nude mice | In vitro: Inhibited cell growth and induced apoptosis |
| Down regulated survivin and XIAP expression | ||||
| In vivo: Inhibited xenograft tumour growth by suppressing JAK2/STAT3 signaling pathway | ||||
| Kumar et al[234] 2015 | miR-let7b and GDC-0449 | microRNA and Hedgehog inhibitor | In vitro: Capan-1, HPAF-II, T3M4 and MIA PaCa-2 cell lines In vivo: Athymic nude mice bearing ectopic tumour | In vitro: Decreased cell proliferation and induced apoptosis via Gli dependent mechanism |
| In vivo: Reduced tumour cell proliferation with increased apoptosis and tumour growth was inhibited | ||||
| Petrova et al[235] 2015 | RU-SKI 43 | Hedgehog acyltransferase inhibitor | In vitro: Pancreatic cancer cell lines In vivo: Panc-1 xenograft mouse model | In vitro: Reduced cancer cell proliferation and Gli-1 activation through Smo independent signaling |
| Decreased Akt and mTOR activity | ||||
| In vivo: Tumour growth decreased | ||||
| Massó-Vallés et al[236] 2015 | Ibrutinib | Tyrosine kinase inhibitor | Transgenic mouse and xenograft mice models | Reduced fibrosis and extended survival |
| Zhou et al[237] 2015 | Zileuton | 5-LOX inhibitor | Pancreatic cancer SW1990 cell line | Induced apoptosis, decreased proliferation and expression of 5-lipoxygenase |
| Lui et al[238] 2015 | Desferrioxamine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and Di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone | Thiosemicarbazones | In vitro: PANC-1 and MIAPaCa-2 In vivo: PANC-1 tumour xenograft mice | Activation of the non-receptor tyrosine kinase Src and cAbl was decreased in vitro and STAT3 activation was reduced in both in vivo and in vitro condition |
| Khan et al[239] 2015 | Ormeloxifene | Nonsteroidal drug | Pancreatic cancer cell lines and PDAC xenograft mice | Inhibited cell proliferation, tumour stroma through SHH pathway and stromal cell infiltration |
| Decreased collagen I expression | ||||
| Restored the tumour-suppressor miR-132 expression | ||||
| Liu et al[240] 2016 | Oridonin | Tetracycline diterpenoid compound | Aspc1, Bxpc3, Panc1 and SW1990 cell lines | Migration and EMT was inhibited by affecting Wnt/β-catenin signal events |
| Haqq et al[241] 2016 | Gemcitabine with omega-3 polyunsaturated fatty acid emulsion, (LipidemTM) | Nucleoside analog | In vitro studies using pancreatic cancer cell lines Capan-1 and Panc-1 and PSC cell line; RLT-PSC | Drugs showed antiproliferative and anti-invasive effects |
| Ji et al[242] 2016 | MMP2 responsive liposome loaded with Pirfenidone and gemcitabine | --- | In vivo: BALB/c nude Orthotopic tumour mice model In vitro: Human PSCs isolated from surgical specimens of Pancreatic cancer | Pirfenidone inhibited collagen I and TGF-β expression in PSCs |
| Gemcitabine killed pancreatic tumour cells |
PSC: Pancreatic stellate cell; TGF-β: Transforming growth factor-β; CCN2: Connective tissue growth factor; NF-κB: Nuclear factor-κB; FAP: Fibroblast activation protein; EMT: Epithelial-mesenchymal transition; MCP-1: Monocyte chemoattractant protein-1; COX-2: Cyclooxygenase-2; PDAC: Pancreatic ductal adenocarcinoma; SHH: Sonic hedgehog; PDGF: Platelet derived growth factor; ALK: Anaplastic lymphoma kinase; MMP: Matrix metalloproteinase; XIAP: X-linked inhibitor of apoptosis protein; IL: Interleukin; HGF: Hepatocyte growth factor; mTOR: Mechanistic target of rapamycin.