AdipoRon and Pancreatic Ductal Adenocarcinoma: a future perspective in overcoming chemotherapy-induced resistance?

Abstract

The latest scientific knowledge has provided additional insights accountable for the worst prognosis for pancreatic ductal adenocarcinoma (PDAC). Among the causative factors, the aptitude to develop resistance towards approved medications denotes the master key for understanding the lack of improvement in PDAC survival over the years. Even though several compounds have achieved encouraging results at preclinical stage, no new adjuvant agents have reached the bedside of PDAC patients lately. The adiponectin receptor agonist AdipoRon is emerging as a promising anticancer drug in different cancer models, particularly in PDAC. Building on the existing findings, we recently reinforced its candidacy in PDAC cells, proposing AdipoRon either as a suitable partner in gemcitabine-based treatment or as an effective drug in resistant cells. Crossing the current state-of-the-art, herein we provide a critical perspective on AdipoRon to figure out whether this receptor agonist can potentially be considered a future therapeutic choice in overcoming chemotherapy-induced resistance, expressly in PDAC.

Keywords

PDAC / AdipoRon / gemcitabine / resistance

References

[1] Park W,O'Reilly EM.Pancreatic cancer: a review.JAMA2021;326:851-62

[2] Sridharan V,Ting DTJAoPC.Landscape of circulating diagnostic biomarkers in pancreatic malignancies. Ann Pancreat Cancer 2020;3:2616-741.

[3] Siegel RL,Fuchs HE.Cancer statistics, 2021.CA Cancer J Clin2021;71:7-33

[4] Palmeri M,Bianchini M.Prognostic impact of conservative surgery for pancreatic IPMNs.Surg Oncol2021;38:101582

[5] Müller PC,Ruzza CM.Neoadjuvant chemotherapy in pancreatic cancer: an appraisal of the current high-level evidence.Pharmacology2021;106:143-53

[6] Conroy T,Hebbar M.Canadian Cancer Trials Group and the Unicancer-GI-PRODIGE GroupFOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer.N Engl J Med2018;379:2395-406

[7] Mehta A,Weekes C.The present and future of systemic and microenvironment-targeted therapy for pancreatic adenocarcinoma.Ann Pancreat Cancer2020;3:3-3 PMCID:PMC7720884

[8] Yu S,Xie KP.Therapeutic resistance of pancreatic cancer: roadmap to its reversal.Biochim Biophys Acta Rev Cancer2021;1875:188461

[9] Tuerhong A,Shi S.Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles’ heel of pancreatic ductal adenocarcinoma.Cell Mol Life Sci2021;78:5505-26

[10] Randazzo O,Pecoraro C.SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance.Cancer Drug Resist2021;4:904-22 PMCID:PMC8992438

[11] Aughton K,Evans A.hENT1 predicts benefit from gemcitabine in pancreatic cancer but only with low CDA mRNA.Cancers (Basel)2021;13:5758 PMCID:PMC8616255

[12] Du J,Li J.Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels.Biosci Rep2020;40:BSR20200401 PMCID:PMC7396420

[13] Saiki Y,Horii A.Attempts to remodel the pathways of gemcitabine metabolism: recent approaches to overcoming tumours with acquired chemoresistance.Cancer Drug Resist2020;3:819-31 PMCID:PMC8992552

[14] Yi-zheng X.Modulation of deoxycytidylate deaminase in intact human leukemia cells.Biochemical Pharmacology1992;44:1819-27

[15] Heinemann V,Chubb S et al.Cellular elimination of 2',2'-difluorodeoxycytidine 5'-triphosphate: a mechanism of self-potentiation.Cancer Res1992;52:533-9

[16] Serdjebi C,Ciccolini J.Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen.Pharmacogenomics2013;14:1047-51

[17] Miller AL,Gamblin TL,Yoon KJ.Development of gemcitabine-resistant patient-derived xenograft models of pancreatic ductal adenocarcinoma.Cancer Drug Resist2020;3:572-85 PMCID:PMC7561044

[18] Weizman N,Shabtay-Orbach A.Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase.Oncogene2014;33:3812-9

[19] Xiao H,Ma L,Sun Q.Clinically-relevant ABC transporter for anti-cancer drug resistance.Front Pharmacol2021;12:648407 PMCID:PMC8089384

[20] Gupta SK,Ali V.Role of membrane-embedded drug efflux ABC transporters in the cancer chemotherapy.Oncol Rev2020;14:448 PMCID:PMC7358983

[21] Xu M,Liu Z.ABCB2 (TAP1) as the downstream target of SHH signaling enhances pancreatic ductal adenocarcinoma drug resistance.Cancer Lett2013;333:152-8

[22] Lu Y,Peng J.HNF1A inhibition induces the resistance of pancreatic cancer cells to gemcitabine by targeting ABCB1.EBioMedicine2019;44:403-18 PMCID:PMC6606897

[23] Okada Y,Takayama T.LAMC2 promotes cancer progression and gemcitabine resistance through modulation of EMT and ATP-binding cassette transporters in pancreatic ductal adenocarcinoma.Carcinogenesis2021;42:546-56 PMCID:PMC8086766

[24] Boyd LNC,Peters GJ,Giovannetti E.Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment.Semin Cancer Biol2022;82:184-96

[25] Jiang B,Lu J.Stroma-targeting therapy in pancreatic cancer: one coin with two sides?.Front Oncol2020;10:576399 PMCID:PMC7593693

[26] Li MJAoPC.Preface for focused issue: science on pancreatic cancer.Ann Pancreat Cancer2020;3:1

[27] Ni Y,Yang J.The role of tumor-stroma interactions in drug resistance within tumor microenvironment.Front Cell Dev Biol2021;9:637675 PMCID:PMC8173135

[28] Comandatore A,Balsano R.Potential role of exosomes in the chemoresistance to gemcitabine and nab-paclitaxel in pancreatic cancer.Diagnostics (Basel)2022;12:286 PMCID:PMC8871170

[29] Grasso C,Giovannetti E.Drug resistance in pancreatic cancer: impact of altered energy metabolism.Crit Rev Oncol Hematol2017;114:139-52

[30] Dai S,Zhu Y.Glycolysis promotes the progression of pancreatic cancer and reduces cancer cell sensitivity to gemcitabine.Biomed Pharmacother2020;121:109521

[31] Masoud R,Lac S.Targeting mitochondrial complex I overcomes chemoresistance in high OXPHOS pancreatic cancer.Cell Rep Med2020;1:100143 PMCID:PMC7691450

[32] Reyes-Castellanos G,Carrier A.Mitochondrial metabolism in PDAC: from better knowledge to new targeting strategies.Biomedicines2020;8:270 PMCID:PMC7460249

[33] Khoramipour K,Hekmatikar AA.Adiponectin: structure, physiological functions, role in diseases, and effects of nutrition.Nutrients2021;13:1180 PMCID:PMC8066826

[34] Esmaili S,Karamian M.Physiological role of adiponectin in different tissues: a review.Arch Physiol Biochem2020;126:67-73

[35] Choi HM,Kim KS.Multifaceted physiological roles of adiponectin in inflammation and diseases.Int J Mol Sci2020;21:1219 PMCID:PMC7072842

[36] Lee YH,Mantzoros CS.Effects of leptin and adiponectin on pancreatic β-cell function.Metabolism2011;60:1664-72

[37] Tao C,Holland WL.Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic β cells and adipocytes.Best Pract Res Clin Endocrinol Metab2014;28:43-58 PMCID:PMC4455885

[38] Winzell MS,Dieguez C.Dual action of adiponectin on insulin secretion in insulin-resistant mice.Biochem Biophys Res Commun2004;321:154-60

[39] Bakhti M.New insights into β-cell failure, regeneration and replacement.Nat Rev Endocrinol2022;18:79-80

[40] Tudurí E,Soriano S.Inhibitory effects of leptin on pancreatic alpha-cell function.Diabetes2009;58:1616-24 PMCID:PMC2699864

[41] Tudurí E,Kara JA,Fox JK.Partial ablation of leptin signaling in mouse pancreatic α-cells does not alter either glucose or lipid homeostasis.Am J Physiol Endocrinol Metab2014;306:E748-55

[42] Elinson N,Birk RZ.Leptin directly regulates exocrine pancreas lipase and two related proteins in the rat.Br J Nutr2006;96:691-6

[43] Jiang CY.Resistin aggravates the expression of proinflammatory cytokines in cerulein-stimulated AR42J pancreatic acinar cells.Mol Med Rep2017;15:502-6

[44] Ramkissoon R.Pancreatic steatosis: an update.Curr Opin Gastroenterol2019;35:440-7

[45] Panagopoulou P,Manolitsas A,Tsitouridis I.Adiponectin and body composition in cystic fibrosis.J Cyst Fibros2008;7:244-51

[46] Polito R,Elce A.Adiponectin expression is modulated by long-term physical activity in adult patients affected by cystic fibrosis.Mediators Inflamm2019;2019:2153934 PMCID:PMC6754935

[47] Liu XX,Li P,Peng XD.Adiponectin is expressed in the pancreas of high-fat-diet-fed mice and protects pancreatic endothelial function during the development of type 2 diabetes.Diabetes Metab2014;40:363-72

[48] Muratore M.Theoretical study of the adiponectin receptors: binding site characterization and molecular dynamics of possible ligands for drug design.SN Appl Sci2020;2

[49] Roy B.Tissue-specific role and associated downstream signaling pathways of adiponectin.Cell Biosci2021;11:77 PMCID:PMC8073961

[50] Rubina KA,Kalinina NI,Balatskiy AV.Revisiting the multiple roles of T-cadherin in health and disease.Eur J Cell Biol2021;100:151183

[51] Jiang J,Zhang W.Adiponectin suppresses human pancreatic cancer growth through attenuating the β-catenin signaling pathway.Int J Biol Sci2019;15:253-64 PMCID:PMC6367542

[52] Kato M,Tsujii M,Shimomura I.Adiponectin inhibits murine pancreatic cancer growth.Dig Dis Sci2014;59:1192-6

[53] Huang B,Wang D.Adiponectin promotes pancreatic cancer progression by inhibiting apoptosis via the activation of AMPK/Sirt1/PGC-1α signaling.Oncotarget2014;5:4732-45 PMCID:PMC4148095

[54] Bao Y,Kraft P.A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts.J Natl Cancer Inst2013;105:95-103 PMCID:PMC3545904

[55] Grote VA,Dossus L.The association of circulating adiponectin levels with pancreatic cancer risk: a study within the prospective EPIC cohort.Int J Cancer2012;130:2428-37

[56] Dimou NL,Mariosa D.CCFREndometrial Cancer Association ConsortiumCirculating adipokine concentrations and risk of five obesity-related cancers: a mendelian randomization study.Int J Cancer2021;148:1625-36 PMCID:PMC7894468

[57] Yang JP,Wang F,Li SL.Association analysis of genetic variants of adiponectin gene and risk of pancreatic cancer.Int J Clin Exp Med2015;8:8094-100 PMCID:PMC4509320

[58] Dalamaga M,Fargnoli JL.Pancreatic cancer expresses adiponectin receptors and is associated with hypoleptinemia and hyperadiponectinemia: a case-control study.Cancer Causes Control2009;20:625-33 PMCID:PMC2720089

[59] Dranka-Bojarowska D,Olakowski M et al.The assessment of serum concentration of adiponectin, leptin and serum carbohydrate antigen-19.9 in patients with pancreatic cancer and chronic pancreatitis.J Physiol Pharmaco2015;66:653-63

[60] Eibl G.Obesity and pancreatic cancer: insight into mechanisms.Cancers (Basel)2021;13:5067 PMCID:PMC8534007

[61] Messaggio F,Castellanos J.Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth.Oncotarget2017;8:85378-91 PMCID:PMC5689616

[62] Kadri Colakoglu M,Ozdemir Y.Roles of adiponectin and leptin as diagnostic markers in pancreatic cancer.Bratisl Lek Listy2017;118:394-8

[63] Zyromski NJ,Pitt HA.Obesity potentiates the growth and dissemination of pancreatic cancer.Surgery2009;146:258-63

[64] Otvos L Jr.Potential adiponectin receptor response modifier therapeutics.Front Endocrinol (Lausanne)2019;10:539 PMCID:PMC6700268

[65] Nigro E,Salzillo A,Naviglio S.AdipoRon and other adiponectin receptor agonists as potential candidates in cancer treatments.Int J Mol Sci2021;22:5569 PMCID:PMC8197554

[66] Sapio L,Ragone A.AdipoRon affects cell cycle progression and inhibits proliferation in human osteosarcoma cells.J Oncol2020;2020:7262479 PMCID:PMC7204133

[67] Okada-Iwabu M,Iwabu M.A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.Nature2013;503:493-9

[68] Akimoto M,Kawabata Y,Takenaga K.Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis.Cell Death Dis2018;9:804 PMCID:PMC6056513

[69] Manley SJ,Jack JL.Synthetic adiponectin-receptor agonist, AdipoRon, induces glycolytic dependence in pancreatic cancer cells.Cell Death Dis2022;13:114 PMCID:PMC8817044

[70] Ragone A,Spina A,Sapio L.Integrating gemcitabine-based therapy with adiporon enhances growth inhibition in human PDAC cell lines.Front Pharmacol2022;13:837503 PMCID:PMC8902254

[71] Takenaga K,Koshikawa N.Obesity reduces the anticancer effect of AdipoRon against orthotopic pancreatic cancer in diet-induced obese mice.Sci Rep2021;11:2923 PMCID:PMC7859201

[72] Latenstein AEJ,Bonsing BA.Dutch Pancreatic Cancer GroupNationwide trends in incidence, treatment and survival of pancreatic ductal adenocarcinoma.Eur J Cancer2020;125:83-93

[73] Mucciolo G,Scagliotti A,Novelli F.The dark side of immunotherapy: pancreatic cancer.Cancer Drug Resist2020;3:491-520 PMCID:PMC8992483

[74] Elsayed M.The latest advancement in pancreatic ductal adenocarcinoma therapy: a review article for the latest guidelines and novel therapies.Biomedicines2021;9:389 PMCID:PMC8067364

[75] Blomstrand H,Bratthäll C,Elander NO.Real world evidence on gemcitabine and nab-paclitaxel combination chemotherapy in advanced pancreatic cancer.BMC Cancer2019;19:40 PMCID:PMC6325739

[76] Hoyer K,Inoue Y.A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: results from the CONKO-005 trial.EBioMedicine2021;66:103327 PMCID:PMC8054140

[77] Santofimia-Castaño P.Combating pancreatic cancer chemoresistance by triggering multiple cell death pathways.Pancreatology2021;21:522-9

[78] Viale A,Lyssiotis CA.Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.Nature2014;514:628-32 PMCID:PMC4376130

[79] Peng J,Xu S.Altered glycolysis results in drug-resistant in clinical tumor therapy.Oncol Lett2021;21:369 PMCID:PMC7967983

[80] Li Petri G,Sciarrillo R.Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds.Br J Cancer2020;123:644-56 PMCID:PMC7434895

[81] Hassouni BE,Capula M.Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction.Oncoscience2020;7:76-80 PMCID:PMC7640902

[82] Matsuura F,Koseki M.Adiponectin accelerates reverse cholesterol transport by increasing high density lipoprotein assembly in the liver.Biochem Biophys Res Commun2007;358:1091-5

[83] Vincent V,Aggarwal S,Ramakrishnan L.ATP-binding cassette transporter A1 (ABCA1) expression in adipose tissue and its modulation with insulin resistance in obesity. Diabetes Metab Syndr Obes 2019;12:275-284 PMCID:PMC6395069