Pancreatic stellate cell: Pandora's box for pancreatic disease biology

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.