Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma.

Cancer drug resistance Cancer treatment Chitinase-3 like 1 Darifenacin Molecular docking Pancreatic cancer

Journal

Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519

Informations de publication

Date de publication:
03 Sep 2024
Historique:
received: 23 04 2024
accepted: 25 08 2024
medline: 3 9 2024
pubmed: 3 9 2024
entrez: 3 9 2024
Statut: aheadofprint

Résumé

Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC. Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort. In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.

Identifiants

DOI: 10.1007/s00280-024-04712-1 PMID: 39225813
pubmed: 39225813
doi: 10.1007/s00280-024-04712-1
pii: 10.1007/s00280-024-04712-1
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024. The Author(s).

Références

Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. CA: a cancer journal for clinicians 73. 117–48. https://doi.org/10.3322/caac.21763
Kunovsky L, Tesarikova P, Kala Z, Kroupa R, Kysela P, Dolina J, Trna J (2018) The use of biomarkers in Early Diagnostics of Pancreatic Cancer. Can J Gastroenterol Hepatol 2018:5389820–5389820. https://doi.org/10.1155/2018/5389820
doi: 10.1155/2018/5389820 pubmed: 30186820 pmcid: 6112218
Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, Maitra A (2023) Pancreatic cancer: advances and challenges. Cell 186(8):1729–1754. https://doi.org/10.1016/j.cell.2023.02.014
doi: 10.1016/j.cell.2023.02.014 pubmed: 37059070 pmcid: 10182830
Sarantis P, Koustas E, Papadimitropoulou A, Papavassiliou AG, Karamouzis MV (2020) Pancreatic ductal adenocarcinoma: treatment hurdles, tumor microenvironment and immunotherapy. World J Gastrointest Oncol 12(2):173–181. https://doi.org/10.4251/wjgo.v12.i2.173
doi: 10.4251/wjgo.v12.i2.173 pubmed: 32104548 pmcid: 7031151
Capula M, Peran M, Xu G, Donati V, Yee D, Gregori A, Assaraf YG, Giovannetti E, Deng D (2022) Role of drug catabolism, modulation of oncogenic signaling and tumor microenvironment in microbe-mediated pancreatic cancer chemoresistance. Drug Resist Updat 64:100864. https://doi.org/10.1016/j.drup.2022.100864
doi: 10.1016/j.drup.2022.100864 pubmed: 36115181
Rebelo R, Xavier CPR, Giovannetti E, Vasconcelos MH (2023) Fibroblasts in pancreatic cancer: molecular and clinical perspectives. Trends Mol Med. https://doi.org/10.1016/j.molmed.2023.03.002
doi: 10.1016/j.molmed.2023.03.002 pubmed: 37100646
Adamska A, Domenichini A, Falasca M (2017) Pancreatic ductal adenocarcinoma: current and evolving therapies. Int J Mol Sci 18(7):1338. https://doi.org/10.3390/ijms18071338
doi: 10.3390/ijms18071338 pubmed: 28640192 pmcid: 5535831
Vogl UM, Andalibi H, Klaus A, Vormittag L, Schima W, Heinrich B, Kafka A, Winkler T, Öhler L (2019) Nab-paclitaxel and gemcitabine or FOLFIRINOX as first-line treatment in patients with unresectable adenocarcinoma of the pancreas: does sequence matter? BMC Cancer 19(1):28–28. https://doi.org/10.1186/s12885-018-5240-6
doi: 10.1186/s12885-018-5240-6 pubmed: 30621630 pmcid: 6325849
Xavier CPR, Castro I, Caires HR, Ferreira D, Cavadas B, Pereira L, Santos LL, Oliveira MJ, Vasconcelos MH (2021) Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine. Cancer Lett 501:210–223. https://doi.org/10.1016/j.canlet.2020.11.013
doi: 10.1016/j.canlet.2020.11.013 pubmed: 33212158
Chen IM, Johansen AZ, Dehlendorff C, Jensen BV, Bojesen SE, Pfeiffer P, Bjerregaard JK, Nielsen SE, Andersen F, Hollander NH, Yilmaz MK, Rasmussen LS, Johansen JS (2020) Prognostic value of combined detection of serum IL6, YKL-40, and C-reactive protein in patients with unresectable pancreatic Cancer. Cancer Epidemiol Biomarkers Prev 29(1):176–184. https://doi.org/10.1158/1055-9965.EPI-19-0672
doi: 10.1158/1055-9965.EPI-19-0672 pubmed: 31685562
Chen HT, Zheng JM, Zhang YZ, Yang M, Wang YL, Man XH, Chen Y, Cai QC, Li ZS (2017) Overexpression of YKL-40 predicts poor prognosis in patients undergoing curative resection of pancreatic Cancer. Pancreas 46(3):323–334. https://doi.org/10.1097/MPA.0000000000000751
doi: 10.1097/MPA.0000000000000751 pubmed: 28099248
Yu JE, Yeo IJ, Han SB, Yun J, Kim B, Yong YJ, Lim YS, Kim TH, Son DJ, Hong JT (2024) Significance of chitinase-3-like protein 1 in the pathogenesis of inflammatory diseases and cancer. Exp Mol Med 56(1):1–18. https://doi.org/10.1038/s12276-023-01131-9
doi: 10.1038/s12276-023-01131-9 pubmed: 38177294 pmcid: 10834487
Chang MC, Chen CT, Chiang PF, Chiang YC (2024) The role of Chitinase-3-like Protein-1 (YKL40) in the therapy of Cancer and other chronic-inflammation-related diseases. Pharmaceuticals (Basel) 17(3). https://doi.org/10.3390/ph17030307
Zhao T, Su Z, Li Y, Zhang X, You Q (2020) Chitinase-3 like-protein-1 function and its role in diseases. Signal Transduct Target Ther 5(1):201. https://doi.org/10.1038/s41392-020-00303-7
doi: 10.1038/s41392-020-00303-7 pubmed: 32929074 pmcid: 7490424
Di Rosa M, Distefano G, Zorena K, Malaguarnera L (2016) Chitinases and immunity: ancestral molecules with new functions. Immunobiology 221(3):399–411. https://doi.org/10.1016/j.imbio.2015.11.014
doi: 10.1016/j.imbio.2015.11.014 pubmed: 26686909
Hakala BE, White C, Recklies AD (1993) Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem 268(34):25803–25810
doi: 10.1016/S0021-9258(19)74461-5 pubmed: 8245017
Renkema GH, Boot RG, Au FL, Donker-Koopman WE, Strijland A, Muijsers AO, Hrebicek M, Aerts JM (1998) Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem 251(1–2):504–509. https://doi.org/10.1046/j.1432-1327.1998.2510504.x
doi: 10.1046/j.1432-1327.1998.2510504.x pubmed: 9492324
Fusetti F, Pijning T, Kalk KH, Bos E, Dijkstra BW (2003) Crystal structure of human cartilage gp39 (HC-gp39) in complex with chitotetraose. https://www.rcsb.org/structure/1NWU
Houston DR, Recklies AD, Krupa JC, van Aalten DM (2003) Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes. J Biol Chem 278(32):30206–30212. https://doi.org/10.1074/jbc.M303371200
doi: 10.1074/jbc.M303371200 pubmed: 12775711
Fusetti F, Pijning T, Kalk KH, Bos E, Dijkstra BW (2003) Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39. J Biol Chem 278(39):37753–37760. https://doi.org/10.1074/jbc.M303137200
doi: 10.1074/jbc.M303137200 pubmed: 12851408
Rebelo R, Polónia B, Santos LL, Vasconcelos MH, Xavier CPR (2021) Drug Repurposing opportunities in Pancreatic Ductal Adenocarcinoma. Pharmaceuticals (Basel) 14(3):280
doi: 10.3390/ph14030280 pubmed: 33804613
Forli S, Huey R, Pique ME, Sanner MF, Goodsell DS, Olson AJ (2016) Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc 11(5):905–919. https://doi.org/10.1038/nprot.2016.051
doi: 10.1038/nprot.2016.051 pubmed: 27077332 pmcid: 4868550
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M (2018) DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 46(D1):D1074–d1082. https://doi.org/10.1093/nar/gkx1037
doi: 10.1093/nar/gkx1037 pubmed: 29126136
Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461. https://doi.org/10.1002/jcc.21334
doi: 10.1002/jcc.21334 pubmed: 19499576 pmcid: 3041641
Seeliger D, de Groot BL (2010) Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des 24(5):417–422. https://doi.org/10.1007/s10822-010-9352-6
doi: 10.1007/s10822-010-9352-6 pubmed: 20401516 pmcid: 2881210
Lill MA, Danielson ML (2011) Computer-aided drug design platform using PyMOL. J Comput Aided Mol Des 25(1):13–19. https://doi.org/10.1007/s10822-010-9395-8
doi: 10.1007/s10822-010-9395-8 pubmed: 21053052
Branco H, Oliveira J, Antunes C, Santos LL, Vasconcelos MH, Xavier CPR (2022) Pirfenidone sensitizes NCI-H460 Non-small Cell Lung Cancer cells to Paclitaxel and to a combination of Paclitaxel with Carboplatin. Int J Mol Sci 23(7). https://doi.org/10.3390/ijms23073631
Rovithi M, Avan A, Funel N, Leon LG, Gomez VE, Wurdinger T, Griffioen AW, Verheul HM, Giovannetti E (2017) Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: a platform for drug testing. Sci Rep 7:44686. https://doi.org/10.1038/srep44686
doi: 10.1038/srep44686 pubmed: 28304379 pmcid: 5356332
Silva BR, Rebelo R, Rodrigues JM, Xavier CPR, Vasconcelos MH, Queiroz MRP (2021) Synthesis of Novel Methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates and antitumor activity evaluation: studies in Vitro and in Ovo grafts of Chick Chorioallantoic membrane (CAM) with a Triple negative breast Cancer Cell line. Molecules 26(6). https://doi.org/10.3390/molecules26061594
Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1(3):1112–1116. https://doi.org/10.1038/nprot.2006.179
doi: 10.1038/nprot.2006.179 pubmed: 17406391
Massihnia D, Avan A, Funel N, Maftouh M, van Krieken A, Granchi C, Raktoe R, Boggi U, Aicher B, Minutolo F, Russo A, Leon LG, Peters GJ, Giovannetti E (2017) Phospho-akt overexpression is prognostic and can be used to tailor the synergistic interaction of akt inhibitors with gemcitabine in pancreatic cancer. J Hematol Oncol 10(1):9. https://doi.org/10.1186/s13045-016-0371-1
doi: 10.1186/s13045-016-0371-1 pubmed: 28061880 pmcid: 5219723
Ali A, Jamieson NB, Khan IN, Chang D, Giovannetti E, Funel N, Frampton AE, Morton J, Sansom O, Evans TRJ, Duthie F, McKay CJ, Samra J, Gill AJ, Biankin A, Oien KA (2022) Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients. Am J Cancer Res 12(12):5668–5683
pubmed: 36628279 pmcid: 9827095
Le Large TYS, El Hassouni B, Funel N, Kok B, Piersma SR, Pham TV, Olive KP, Kazemier G, van Laarhoven HWM, Jimenez CR, Bijlsma MF, Giovannetti E (2019) Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment. Ther Adv Med Oncol 11:1758835919841233. https://doi.org/10.1177/1758835919841233
doi: 10.1177/1758835919841233 pubmed: 31205498 pmcid: 6535709
Song P, Sekhon HS, Lu A, Arredondo J, Sauer D, Gravett C, Mark GP, Grando SA, Spindel ER (2007) M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion. Cancer Res 67(8):3936–3944. https://doi.org/10.1158/0008-5472.CAN-06-2484
doi: 10.1158/0008-5472.CAN-06-2484 pubmed: 17440109
Crystal structure of human cartilage (2003) gp39 (HC-gp39) in complex with chitotetraose https://www.rcsb.org/structure/1NWU
Kognole AA, Payne CM (2017) Inhibition of mammalian glycoprotein YKL-40: IDENTIFICATION OF THE PHYSIOLOGICAL LIGAND. J Biol Chem 292(7):2624–2636. https://doi.org/10.1074/jbc.M116.764985
doi: 10.1074/jbc.M116.764985 pubmed: 28053085 pmcid: 5314161
Lee IA, Kamba A, Low D, Mizoguchi E (2014) Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease. World J Gastroenterol 20(5):1127–1138. https://doi.org/10.3748/wjg.v20.i5.1127
doi: 10.3748/wjg.v20.i5.1127 pubmed: 24574789 pmcid: 3921497
Zadi Heydarabad M, Baharaghdam S, Azimi A, Mohammadi H, Eivazi Ziaei J, Yazdanpanah B, Zak MS, Farahani ME, Dohrabpour A, Partash N, Talebi M (2019) The role of tumor suppressor of resveratrol and prednisolone by downregulation of YKL-40 expression in CCRF-CEM cell line. J Cell Biochem 120(3):3773–3779. https://doi.org/10.1002/jcb.27659
doi: 10.1002/jcb.27659 pubmed: 30426549
Zhang W, Murao K, Zhang X, Matsumoto K, Diah S, Okada M, Miyake K, Kawai N, Fei Z, Tamiya T (2010) Resveratrol represses YKL-40 expression in human glioma U87 cells. BMC Cancer 10:593. https://doi.org/10.1186/1471-2407-10-593
doi: 10.1186/1471-2407-10-593 pubmed: 21029458 pmcid: 2988030
Rao FV, Andersen OA, Vora KA, Demartino JA, van Aalten DM (2005) Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes. Chem Biol 12(9):973–980. https://doi.org/10.1016/j.chembiol.2005.07.009
doi: 10.1016/j.chembiol.2005.07.009 pubmed: 16183021
Yamada S, Ito Y, Nishijima S, Kadekawa K, Sugaya K (2018) Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder. Pharmacol Ther 189:130–148. https://doi.org/10.1016/j.pharmthera.2018.04.010
doi: 10.1016/j.pharmthera.2018.04.010 pubmed: 29709423
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703. https://doi.org/10.1056/NEJMoa1304369
doi: 10.1056/NEJMoa1304369
Geng B, Pan J, Zhao T, Ji J, Zhang C, Che Y, Yang J, Shi H, Li J, Zhou H, Mu X, Xu C, Wang C, Xu Y, Liu Z, Wen H, You Q (2018) Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through beta-catenin/Erk/Akt signaling in gastric cancer. J Exp Clin Cancer Res 37(1):208. https://doi.org/10.1186/s13046-018-0876-2
doi: 10.1186/s13046-018-0876-2 pubmed: 30165890 pmcid: 6117920
Yamada S, Ito Y, Nishijima S, Kadekawa K, Sugaya K (2018) Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder. Pharmacol Ther 189:130–148. https://doi.org/10.1016/j.pharmthera.2018.04.010
doi: 10.1016/j.pharmthera.2018.04.010 pubmed: 29709423
Su PC, Chen CY, Yu MH, Kuo IY, Yang PS, Hsu CH, Hou YC, Hsieh HT, Chang CP, Shan YS, Wang YC (2024) Fully human chitinase-3 like-1 monoclonal antibody inhibits tumor growth, fibrosis, angiogenesis, and immune cell remodeling in lung, pancreatic, and colorectal cancers. Biomed Pharmacother 176:116825. https://doi.org/10.1016/j.biopha.2024.116825
doi: 10.1016/j.biopha.2024.116825 pubmed: 38820971
Zinner N, Kobashi KC, Ebinger U, Viegas A, Egermark M, Quebe-Fehling E, Koochaki P (2008) Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract 62(11):1664–1674. https://doi.org/10.1111/j.1742-1241.2008.01893.x
doi: 10.1111/j.1742-1241.2008.01893.x pubmed: 18811599
Hering NA, Liu V, Kim R, Weixler B, Droeser RA, Arndt M, Pozios I, Beyer K, Kreis ME, Seeliger H (2021) Blockage of Cholinergic Signaling via Muscarinic Acetylcholine Receptor 3 inhibits Tumor Growth in Human Colorectal Adenocarcinoma. Cancers 13(13):3220. https://doi.org/10.3390/cancers13133220
doi: 10.3390/cancers13133220 pubmed: 34203220 pmcid: 8267754
Yang T, He W, Cui F, Xia J, Zhou R, Wu Z, Zhao Y, Shi M (2016) MACC1 mediates acetylcholine-induced invasion and migration by human gastric cancer cells. Oncotarget 7(14):18085–18094. https://doi.org/10.18632/oncotarget.7634
doi: 10.18632/oncotarget.7634 pubmed: 26919111 pmcid: 4951273
Yu H, Xia H, Tang Q, Xu H, Wei G, Chen Y, Dai X, Gong Q, Bi F (2017) Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation. Sci Rep 7:40802. https://doi.org/10.1038/srep40802
doi: 10.1038/srep40802 pubmed: 28102288 pmcid: 5244394
Song P, Sekhon HS, Fu XW, Maier M, Jia Y, Duan J, Proskosil BJ, Gravett C, Lindstrom J, Mark GP, Saha S, Spindel ER (2008) Activated cholinergic signaling provides a target in squamous cell lung carcinoma. Cancer Res 68(12):4693–4700. https://doi.org/10.1158/0008-5472.CAN-08-0183
doi: 10.1158/0008-5472.CAN-08-0183 pubmed: 18559515 pmcid: 2865551
Sipos B, Moser S, Kalthoff H, Torok V, Lohr M, Kloppel G (2003) A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. Virchows Arch 442(5):444–452. https://doi.org/10.1007/s00428-003-0784-4
doi: 10.1007/s00428-003-0784-4 pubmed: 12692724
Bhatia K, Bhumika, Das A (2020) Combinatorial drug therapy in cancer - new insights. Life Sci 258:118134. https://doi.org/10.1016/j.lfs.2020.118134
doi: 10.1016/j.lfs.2020.118134 pubmed: 32717272
Matera C, Tata AM (2014) Pharmacological approaches to targeting muscarinic acetylcholine receptors. Recent Pat CNS Drug Discov 9(2):85–100. https://doi.org/10.2174/1574889809666141120131238
doi: 10.2174/1574889809666141120131238 pubmed: 25413004
Schledwitz A, Sundel MH, Alizadeh M, Hu S, Xie G, Raufman JP (2021) Differential actions of muscarinic receptor subtypes in gastric, pancreatic, and Colon cancer. Int J Mol Sci 22(23). https://doi.org/10.3390/ijms222313153
Kruse AC, Kobilka BK, Gautam D, Sexton PM, Christopoulos A, Wess J (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13(7):549–560. https://doi.org/10.1038/nrd4295
doi: 10.1038/nrd4295 pubmed: 24903776 pmcid: 5818261
Chapple CR (2004) Darifenacin: a novel M3 muscarinic selective receptor antagonist for the treatment of overactive bladder. Expert Opin Investig Drugs 13(11):1493–1500. https://doi.org/10.1517/13543784.13.11.1493
doi: 10.1517/13543784.13.11.1493 pubmed: 15500396
Zhang L, Xiu D, Zhan J, He X, Guo L, Wang J, Tao M, Fu W, Zhang H (2016) High expression of muscarinic acetylcholine receptor 3 predicts poor prognosis in patients with pancreatic ductal adenocarcinoma. Onco Targets Ther 9:6719–6726. https://doi.org/10.2147/OTT.S111382
doi: 10.2147/OTT.S111382 pubmed: 27826198 pmcid: 5096762

Auteurs

Sofia M Sousa (SM)

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal.
Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal.
LQOF - Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal.

Helena Branco (H)

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal.
Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal.

Amir Avan (A)

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, 91886-17871, Iran.
Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, 91886-17871, Iran.

Andreia Palmeira (A)

LQOF - Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal.
CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Terminal de Cruzeiros do Porto de Leixões, Matosinhos, 4450-208, Portugal.

Luca Morelli (L)

General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, 56100, Italy.

Lúcio L Santos (LL)

Experimental Pathology and Therapeutics Research Group and Surgical Oncology Department, IPO-Instituto Português de Oncologia, Rua Dr. António Bernardino de Almeida 865, Porto, 4200-072, Portugal.
ICBAS-UP-School of Medicine and Biomedical Sciences, University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050- 313, Portugal.

Elisa Giovannetti (E)

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, HV Amsterdam, 1081, The Netherlands.
Cancer Pharmacology Lab, Fondazione Pisana per La Scienza, San Giuliano, 56017, Italy.

M Helena Vasconcelos (MH)

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal. hvasconcelos@ipatimup.pt.
Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal. hvasconcelos@ipatimup.pt.
Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal. hvasconcelos@ipatimup.pt.
ORCID: 0000-0002-7801-4643

Cristina P R Xavier (CPR)

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal. cristina.xavier@iucs.cespu.pt.
Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal. cristina.xavier@iucs.cespu.pt.
UCIBIO - Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), Gandra, 4585-116, Portugal. cristina.xavier@iucs.cespu.pt.
Associate Laboratory i4HB - Institute for Health and Bioeconomy, University Institute of Health Sciences - CESPU, Gandra, 4585-116, Portugal. cristina.xavier@iucs.cespu.pt.
ORCID: 0000-0002-4613-1917

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