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Mini-Reviews in Medicinal Chemistry

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ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

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Mini-Review Article

Pharmacological Modulation of Apoptosis and Autophagy in Pancreatic Cancer Treatment

Author(s): Nityaa Selvarajoo, Johnson Stanslas*, Mohammad Kaisarul Islam*, Sreenivasa Rao Sagineedu, Ho Kok Lian and Jonathan Chee Woei Lim

Volume 22, Issue 20, 2022

Published on: 15 July, 2022

Page: [2581 - 2595] Pages: 15

DOI: 10.2174/1389557522666220324123605

Price: $65

Abstract

Background: Pancreatic cancer is a fatal malignant neoplasm with infrequent signs and symptoms until a progressive stage. In 2020, GLOBOCAN reported that pancreatic cancer accounts for 4.7% of all cancer deaths. Despite the availability of standard chemotherapy regimens for treatment, the survival benefits are not guaranteed because tumor cells become chemoresistant even due to the development of chemoresistance in tumor cells even with a short treatment course, where apoptosis and autophagy play critical roles.

Objective: This review compiled essential information on the regulatory mechanisms and roles of apoptosis and autophagy in pancreatic cancer, as well as drug-like molecules that target different pathways in pancreatic cancer eradication, with an aim to provide ideas to the scientific communities in discovering novel and specific drugs to treat pancreatic cancer, specifically PDAC.

Method: Electronic databases that were searched for research articles for this review were Scopus, Science Direct, PubMed, Springer Link, and Google Scholar. The published studies were identified and retrieved using selected keywords.

Discussion/Conclusion: Many small-molecule anticancer agents have been developed to regulate autophagy and apoptosis associated with pancreatic cancer treatment, where most of them target apoptosis directly through EGFR/Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. The cancer drugs that regulate autophagy in treating cancer can be categorized into three groups: i) direct autophagy inducers (e.g., rapamycin), ii) indirect autophagy inducers (e.g., resveratrol), and iii) autophagy inhibitors. Resveratrol persuades both apoptosis and autophagy with a cytoprotective effect, while autophagy inhibitors (e.g., 3-methyladenine, chloroquine) can turn off the protective autophagic effect for therapeutic benefits. Several studies showed that autophagy inhibition resulted in a synergistic effect with chemotherapy (e.g., a combination of metformin with gemcitabine/ 5FU). Such drugs possess a unique clinical value in treating pancreatic cancer as well as other autophagy-dependent carcinomas.

Keywords: Pancreatic cancer, apoptosis, autophagy, chemoresistance, autophagy modulators, cancer drugs.

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[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN Esti-mates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[PMID: 33538338]
[2]
Rawla, P.; Sunkara, T.; Gaduputi, V. Epidemiology of pancreatic cancer: Global trends, etiology and risk factors. World J. Oncol., 2019, 10(1), 10-27.
[http://dx.doi.org/10.14740/wjon1166] [PMID: 30834048]
[3]
Onorati, A.V.; Dyczynski, M.; Ojha, R.; Amaravadi, R.K. Targeting autophagy in cancer. Cancer, 2018, 124(16), 3307-3318.
[http://dx.doi.org/10.1002/cncr.31335] [PMID: 29671878]
[4]
Hidalgo, M.; Cascinu, S.; Kleeff, J.; Labianca, R.; Löhr, J.M.; Neoptolemos, J.; Real, F.X.; Van Laethem, J.L.; Heinemann, V. Addressing the challenges of pancreatic cancer: Future directions for improving outcomes. Pancreatology, 2015, 15(1), 8-18.
[http://dx.doi.org/10.1016/j.pan.2014.10.001] [PMID: 25547205]
[5]
Malvezzi, M.; Carioli, G.; Bertuccio, P.; Boffetta, P.; Levi, F.; La Vecchia, C.; Negri, E. European cancer mortality predictions for the year 2019 with focus on breast cancer. Ann. Oncol., 2019, 30(5), 781-787.
[http://dx.doi.org/10.1093/annonc/mdz051] [PMID: 30887043]
[6]
Sunami, Y.; Kleeff, J. Immunotherapy of pancreatic cancer. Prog. Mol. Biol. Transl. Sci., 2019, 164, 189-216.
[http://dx.doi.org/10.1016/bs.pmbts.2019.03.006] [PMID: 31383405]
[7]
Bryant, K.L.; Mancias, J.D.; Kimmelman, A.C.; Der, C.J. KRAS: Feeding pancreatic cancer proliferation. Trends Biochem. Sci., 2014, 39(2), 91-100.
[http://dx.doi.org/10.1016/j.tibs.2013.12.004] [PMID: 24388967]
[8]
Papademetrio, D.L.; Lompardía, S.L.; Simunovich, T.; Costantino, S.; Mihalez, C.Y.; Cavaliere, V.; Álvarez, É. Inhibition of survival pathways MAPK and NF-kB triggers apoptosis in pancreatic ductal adenocarcinoma cells via suppression of autophagy. Target. Oncol., 2016, 11(2), 183-195.
[http://dx.doi.org/10.1007/s11523-015-0388-3] [PMID: 26373299]
[9]
Lowe, S.W.; Cepero, E.; Evan, G. Intrinsic tumour suppression. Nature, 2004, 432(7015), 307-315.
[http://dx.doi.org/10.1038/nature03098] [PMID: 15549092]
[10]
Arlt, A.; Müerköster, S.S.; Schäfer, H. Targeting apoptosis pathways in pancreatic cancer. Cancer Lett., 2013, 332(2), 346-358.
[http://dx.doi.org/10.1016/j.canlet.2010.10.015] [PMID: 21078544]
[11]
Jia, L-T.; Chen, S-Y.; Yang, A-G. Cancer gene therapy targeting cellular apoptosis machinery. Cancer Treat. Rev., 2012, 38(7), 868-876.
[http://dx.doi.org/10.1016/j.ctrv.2012.06.008] [PMID: 22800735]
[12]
Shintani, T.; Klionsky, D.J. Autophagy in health and disease: A double-edged sword. Science, 2004, 306(5698), 990-995.
[http://dx.doi.org/10.1126/science.1099993] [PMID: 15528435]
[13]
Gump, J.M.; Thorburn, A. Autophagy and apoptosis: What is the connection? Trends Cell Biol., 2011, 21(7), 387-392.
[http://dx.doi.org/10.1016/j.tcb.2011.03.007] [PMID: 21561772]
[14]
Nagelkerke, A.; Bussink, J.; Geurts-Moespot, A.; Sweep, F.C.; Span, P.N. Therapeutic targeting of autophagy in cancer. Part II: Pharmaco-logical modulation of treatment-induced autophagy. Semin. Cancer Biol., 2015, 31, 99-105.
[http://dx.doi.org/10.1016/j.semcancer.2014.06.001] [PMID: 24933034]
[15]
Kurata, N.; Fujita, H.; Ohuchida, K.; Mizumoto, K.; Mahawithitwong, P.; Sakai, H.; Onimaru, M.; Manabe, T.; Ohtsuka, T.; Tanaka, M. Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil. Int. J. Oncol., 2011, 39(2), 473-482.
[PMID: 21617862]
[16]
de Sousa Cavalcante, L.; Monteiro, G. Gemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur. J. Pharmacol., 2014, 741, 8-16.
[http://dx.doi.org/10.1016/j.ejphar.2014.07.041] [PMID: 25084222]
[17]
Nakano, Y.; Tanno, S.; Koizumi, K.; Nishikawa, T.; Nakamura, K.; Minoguchi, M.; Izawa, T.; Mizukami, Y.; Okumura, T.; Kohgo, Y. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br. J. Cancer, 2007, 96(3), 457-463.
[http://dx.doi.org/10.1038/sj.bjc.6603559] [PMID: 17224927]
[18]
Duxbury, M.S.; Ito, H.; Benoit, E.; Zinner, M.J.; Ashley, S.W.; Whang, E.E. Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancer. Surgery, 2004, 136(2), 261-269.
[http://dx.doi.org/10.1016/j.surg.2004.04.029] [PMID: 15300189]
[19]
Philip, P.A.; Benedetti, J.; Corless, C.L.; Wong, R.; O’Reilly, E.M.; Flynn, P.J.; Rowland, K.M.; Atkins, J.N.; Mirtsching, B.C.; Rivkin, S.E.; Khorana, A.A.; Goldman, B.; Fenoglio-Preiser, C.M.; Abbruzzese, J.L.; Blanke, C.D. Phase III study comparing gemcitabine plus cetuxi-mab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J. Clin. Oncol., 2010, 28(22), 3605-3610.
[http://dx.doi.org/10.1200/JCO.2009.25.7550] [PMID: 20606093]
[20]
Yardley, D.A. nab-Paclitaxel mechanisms of action and delivery. J. Control. Release, 2013, 170(3), 365-372.
[http://dx.doi.org/10.1016/j.jconrel.2013.05.041] [PMID: 23770008]
[21]
Desai, N.; Trieu, V.; Damascelli, B.; Soon-Shiong, P. SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Transl. Oncol., 2009, 2(2), 59-64.
[http://dx.doi.org/10.1593/tlo.09109] [PMID: 19412420]
[22]
Grasso, C.; Jansen, G.; Giovannetti, E. Drug resistance in pancreatic cancer: Impact of altered energy metabolism. Crit. Rev. Oncol. Hematol., 2017, 114, 139-152.
[http://dx.doi.org/10.1016/j.critrevonc.2017.03.026] [PMID: 28477742]
[23]
Hamacher, R.; Schmid, R.M.; Saur, D.; Schneider, G. Apoptotic pathways in pancreatic ductal adenocarcinoma. Mol. Cancer, 2008, 7(1), 64.
[http://dx.doi.org/10.1186/1476-4598-7-64] [PMID: 18652674]
[24]
Reichert, M.; Rustgi, A.K. Pancreatic ductal cells in development, regeneration, and neoplasia. J. Clin. Invest., 2011, 121(12), 4572-4578.
[http://dx.doi.org/10.1172/JCI57131] [PMID: 22133881]
[25]
Ghaneh, P.; Costello, E.; Neoptolemos, J.P. Biology and management of pancreatic cancer. Gut, 2007, 56(8), 1134-1152.
[PMID: 17625148]
[26]
Means, A.L.; Meszoely, I.M.; Suzuki, K.; Miyamoto, Y.; Rustgi, A.K.; Coffey, R.J., Jr; Wright, C.V.; Stoffers, D.A.; Leach, S.D. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development, 2005, 132(16), 3767-3776.
[http://dx.doi.org/10.1242/dev.01925] [PMID: 16020518]
[27]
Zhu, L.; Shi, G.; Schmidt, C.M.; Hruban, R.H.; Konieczny, S.F. Acinar cells contribute to the molecular heterogeneity of pancreatic in-traepithelial neoplasia. Am. J. Pathol., 2007, 171(1), 263-273.
[http://dx.doi.org/10.2353/ajpath.2007.061176] [PMID: 17591971]
[28]
Rovira, M.; Scott, S.G.; Liss, A.S.; Jensen, J.; Thayer, S.P.; Leach, S.D. Isolation and characterization of centroacinar/terminal ductal pro-genitor cells in adult mouse pancreas. Proc. Natl. Acad. Sci. USA, 2010, 107(1), 75-80.
[http://dx.doi.org/10.1073/pnas.0912589107] [PMID: 20018761]
[29]
Bardeesy, N.; DePinho, R.A. Pancreatic cancer biology and genetics. Nat. Rev. Cancer, 2002, 2(12), 897-909.
[http://dx.doi.org/10.1038/nrc949] [PMID: 12459728]
[30]
Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol., 2001, 2(2), 127-137.
[http://dx.doi.org/10.1038/35052073] [PMID: 11252954]
[31]
Wong, H.H.; Lemoine, N.R. Pancreatic cancer: Molecular pathogenesis and new therapeutic targets. Nat. Rev. Gastroenterol. Hepatol., 2009, 6(7), 412-422.
[http://dx.doi.org/10.1038/nrgastro.2009.89] [PMID: 19506583]
[32]
Deramaudt, T.; Rustgi, A.K. Mutant KRAS in the initiation of pancreatic cancer. Biochim. Biophys. Acta, 2005, 1756(2), 97-101.
[PMID: 16169155]
[33]
Cohenuram, M.; Saif, M.W. Epidermal growth factor receptor inhibition strategies in pancreatic cancer: Past, present and the future. JOP, 2007, 8(1), 4-15.
[PMID: 17228128]
[34]
Cheng, J.Q.; Ruggeri, B.; Klein, W.M.; Sonoda, G.; Altomare, D.A.; Watson, D.K.; Testa, J.R. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl. Acad. Sci. USA, 1996, 93(8), 3636-3641.
[http://dx.doi.org/10.1073/pnas.93.8.3636] [PMID: 8622988]
[35]
Ruggeri, B.A.; Huang, L.; Wood, M.; Cheng, J.Q.; Testa, J.R. Amplification and overexpression of the AKT2 oncogene in a subset of hu-man pancreatic ductal adenocarcinomas. Mol. Carcinog., 1998, 21(2), 81-86.
[http://dx.doi.org/10.1002/(SICI)1098-2744(199802)21:2<81:AID-MC1>3.0.CO;2-R] [PMID: 9496907]
[36]
Altomare, D.A.; Tanno, S.; De Rienzo, A.; Klein-Szanto, A.J.; Tanno, S.; Skele, K.L.; Hoffman, J.P.; Testa, J.R. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J. Cell. Biochem., 2002, 87(4), 470-476.
[http://dx.doi.org/10.1002/jcb.10287] [PMID: 14735903]
[37]
Schlieman, M.G.; Fahy, B.N.; Ramsamooj, R.; Beckett, L.; Bold, R.J. Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br. J. Cancer, 2003, 89(11), 2110-2115.
[http://dx.doi.org/10.1038/sj.bjc.6601396] [PMID: 14647146]
[38]
Asano, T.; Yao, Y.; Zhu, J.; Li, D.; Abbruzzese, J.L.; Reddy, S.A. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene, 2004, 23(53), 8571-8580.
[http://dx.doi.org/10.1038/sj.onc.1207902] [PMID: 15467756]
[39]
Xu, X.; Ehdaie, B.; Ohara, N.; Yoshino, T.; Deng, C.X. Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarci-noma formation in mice. Oncogene, 2010, 29(5), 674-686.
[http://dx.doi.org/10.1038/onc.2009.375] [PMID: 19901970]
[40]
Modi, S.; Kir, D.; Banerjee, S.; Saluja, A. Control of apoptosis in treatment and biology of pancreatic cancer. J. Cell. Biochem., 2016, 117(2), 279-288.
[http://dx.doi.org/10.1002/jcb.25284] [PMID: 26206252]
[41]
Wong, R.S. Apoptosis in cancer: From pathogenesis to treatment. J. Exp. Clin. Cancer Res., 2011, 30(1), 87.
[http://dx.doi.org/10.1186/1756-9966-30-87] [PMID: 21943236]
[42]
Gesto, D.S.; Cerqueira, N.M.F.S.A.; Fernandes, P.A.; Ramos, M.J. Gemcitabine: A critical nucleoside for cancer therapy. Curr. Med. Chem., 2012, 19(7), 1076-1087.
[http://dx.doi.org/10.2174/092986712799320682] [PMID: 22257063]
[43]
Moysan, E.; Bastiat, G.; Benoit, J.P. Gemcitabine versus modified gemcitabine: A review of several promising chemical modifications. Mol. Pharm., 2013, 10(2), 430-444.
[http://dx.doi.org/10.1021/mp300370t] [PMID: 22978251]
[44]
Huang, P.; Plunkett, W. Induction of apoptosis by gemcitabine. Semin. Oncol., 1995, 22(4)(Suppl. 11), 19-25.
[PMID: 7481840]
[45]
Papademetrio, D.L.; Cavaliere, V.; Simunovich, T.; Costantino, S.; Campos, M.D.; Lombardo, T.; Kaiser, C.M.; Alvarez, E. Interplay bet-ween autophagy and apoptosis in pancreatic tumors in response to gemcitabine. Target. Oncol., 2014, 9(2), 123-134.
[http://dx.doi.org/10.1007/s11523-013-0278-5] [PMID: 23588416]
[46]
Goldstein, D.; El-Maraghi, R.H.; Hammel, P.; Heinemann, V.; Kunzmann, V.; Sastre, J.; Scheithauer, W.; Siena, S.; Tabernero, J.; Teixeira, L.; Tortora, G.; Van Laethem, J.L.; Young, R.; Penenberg, D.N.; Lu, B.; Romano, A.; Von Hoff, D.D. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: Long-term survival from a phase III trial. J. Natl. Cancer Inst., 2015, 107(2), dju413.
[http://dx.doi.org/10.1093/jnci/dju413] [PMID: 25638248]
[47]
Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic ductal adenocarcinoma: Current and evolving therapies. Int. J. Mol. Sci., 2017, 18(7), 1338.
[http://dx.doi.org/10.3390/ijms18071338] [PMID: 28640192]
[48]
Dong, Q.G.; Sclabas, G.M.; Fujioka, S.; Schmidt, C.; Peng, B.; Wu, T.; Tsao, M.S.; Evans, D.B.; Abbruzzese, J.L.; McDonnell, T.J.; Chiao, P.J. The function of multiple IkappaB: NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene, 2002, 21(42), 6510-6519.
[http://dx.doi.org/10.1038/sj.onc.1205848] [PMID: 12226754]
[49]
Suker, M.; Beumer, B.R.; Sadot, E.; Marthey, L.; Faris, J.E.; Mellon, E.A.; El-Rayes, B.F.; Wang-Gillam, A.; Lacy, J.; Hosein, P.J.; Moor-craft, S.Y.; Conroy, T.; Hohla, F.; Allen, P.; Taieb, J.; Hong, T.S.; Shridhar, R.; Chau, I.; van Eijck, C.H.; Koerkamp, B.G. FOLFIRINOX for locally advanced pancreatic cancer: A systematic review and patient-level meta-analysis. Lancet Oncol., 2016, 17(6), 801-810.
[http://dx.doi.org/10.1016/S1470-2045(16)00172-8] [PMID: 27160474]
[50]
Faris, J.E.; Blaszkowsky, L.S.; McDermott, S.; Guimaraes, A.R.; Szymonifka, J.; Huynh, M.A.; Ferrone, C.R.; Wargo, J.A.; Allen, J.N.; Dias, L.E.; Kwak, E.L.; Lillemoe, K.D.; Thayer, S.P.; Murphy, J.E.; Zhu, A.X.; Sahani, D.V.; Wo, J.Y.; Clark, J.W.; Fernandez-del Castillo, C.; Ryan, D.P.; Hong, T.S. FOLFIRINOX in locally advanced pancreatic cancer: The Massachusetts General Hospital Cancer Center expe-rience. Oncologist, 2013, 18(5), 543-548.
[http://dx.doi.org/10.1634/theoncologist.2012-0435] [PMID: 23657686]
[51]
Li, J.; Hou, N.; Faried, A.; Tsutsumi, S.; Takeuchi, T.; Kuwano, H. Inhibition of autophagy by 3-MA enhances the effect of 5-FU-induced apoptosis in colon cancer cells. Ann. Surg. Oncol., 2009, 16(3), 761-771.
[http://dx.doi.org/10.1245/s10434-008-0260-0] [PMID: 19116755]
[52]
Ouyang, G.; Liu, Z.; Huang, S.; Li, Q.; Xiong, L.; Miao, X.; Wen, Y. Gemcitabine plus cisplatin versus gemcitabine alone in the treatment of pancreatic cancer: A meta-analysis. World J. Surg. Oncol., 2016, 14(1), 59.
[http://dx.doi.org/10.1186/s12957-016-0813-9] [PMID: 26927942]
[53]
Baldo, P.; Cecco, S.; Giacomin, E.; Lazzarini, R.; Ros, B.; Marastoni, S. mTOR pathway and mTOR inhibitors as agents for cancer therapy. Curr. Cancer Drug Targets, 2008, 8(8), 647-665.
[http://dx.doi.org/10.2174/156800908786733513] [PMID: 19075588]
[54]
Bayraktar, S.; Rocha-Lima, C.M. Advanced or metastatic pancreatic cancer: Molecular targeted therapies. Mt. Sinai J. Med., 2010, 77(6), 606-619.
[http://dx.doi.org/10.1002/msj.20217] [PMID: 21105124]
[55]
Siu, L.L.; Awada, A.; Takimoto, C.H.; Piccart, M.; Schwartz, B.; Giannaris, T.; Lathia, C.; Petrenciuc, O.; Moore, M.J. Phase I trial of sora-fenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin. Cancer Res., 2006, 12(1), 144-151.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-1571] [PMID: 16397036]
[56]
Scholl, C.; Fröhling, S.; Dunn, I.F.; Schinzel, A.C.; Barbie, D.A.; Kim, S.Y.; Silver, S.J.; Tamayo, P.; Wadlow, R.C.; Ramaswamy, S.; Döh-ner, K.; Bullinger, L.; Sandy, P.; Boehm, J.S.; Root, D.E.; Jacks, T.; Hahn, W.C.; Gilliland, D.G. Synthetic lethal interaction between onco-genic KRAS dependency and STK33 suppression in human cancer cells. Cell, 2009, 137(5), 821-834.
[http://dx.doi.org/10.1016/j.cell.2009.03.017] [PMID: 19490892]
[57]
Zhang, W.; Nandakumar, N.; Shi, Y.; Manzano, M.; Smith, A.; Graham, G.; Gupta, S.; Vietsch, E.E.; Laughlin, S.Z.; Wadhwa, M.; Che-tram, M.; Joshi, M.; Wang, F.; Kallakury, B.; Toretsky, J.; Wellstein, A.; Yi, C. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci. Signal., 2014, 7(324), ra42.
[http://dx.doi.org/10.1126/scisignal.2005049] [PMID: 24803537]
[58]
Maurer, T.; Garrenton, L.S.; Oh, A.; Pitts, K.; Anderson, D.J.; Skelton, N.J.; Fauber, B.P.; Pan, B.; Malek, S.; Stokoe, D.; Ludlam, M.J.; Bowman, K.K.; Wu, J.; Giannetti, A.M.; Starovasnik, M.A.; Mellman, I.; Jackson, P.K.; Rudolph, J.; Wang, W.; Fang, G. Small-molecule li-gands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl. Acad. Sci. USA, 2012, 109(14), 5299-5304.
[http://dx.doi.org/10.1073/pnas.1116510109] [PMID: 22431598]
[59]
Spiegel, J.; Cromm, P.M.; Zimmermann, G.; Grossmann, T.N.; Waldmann, H. Small-molecule modulation of Ras signaling. Nat. Chem. Biol., 2014, 10(8), 613-622.
[http://dx.doi.org/10.1038/nchembio.1560] [PMID: 24929527]
[60]
Wolpin, B.M.; Hezel, A.F.; Abrams, T.; Blaszkowsky, L.S.; Meyerhardt, J.A.; Chan, J.A.; Enzinger, P.C.; Allen, B.; Clark, J.W.; Ryan, D.P.; Fuchs, C.S. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J. Clin. Oncol., 2009, 27(2), 193-198.
[http://dx.doi.org/10.1200/JCO.2008.18.9514] [PMID: 19047305]
[61]
Nagelkerke, A.; Sweep, F.C.; Geurts-Moespot, A.; Bussink, J.; Span, P.N. Therapeutic targeting of autophagy in cancer. Part I: Molecular pathways controlling autophagy. Semin. Cancer Biol., 2015, 31, 89-98.
[http://dx.doi.org/10.1016/j.semcancer.2014.05.004] [PMID: 24879905]
[62]
Yang, S.; Wang, X.; Contino, G.; Liesa, M.; Sahin, E.; Ying, H.; Bause, A.; Li, Y.; Stommel, J.M.; Dell’antonio, G.; Mautner, J.; Tonon, G.; Haigis, M.; Shirihai, O.S.; Doglioni, C.; Bardeesy, N.; Kimmelman, A.C. Pancreatic cancers require autophagy for tumor growth. Genes Dev., 2011, 25(7), 717-729.
[http://dx.doi.org/10.1101/gad.2016111] [PMID: 21406549]
[63]
Cohignac, V.; Landry, M.J.; Boczkowski, J.; Lanone, S. Autophagy as a possible underlying mechanism of nanomaterial toxicity. Nanomaterials (Basel), 2014, 4(3), 548-582.
[http://dx.doi.org/10.3390/nano4030548] [PMID: 28344236]
[64]
Seront, E.; Boidot, R.; Bouzin, C.; Karroum, O.; Jordan, B.F.; Gallez, B.; Machiels, J.P.; Feron, O. Tumour hypoxia determines the poten-tial of combining mTOR and autophagy inhibitors to treat mammary tumours. Br. J. Cancer, 2013, 109(10), 2597-2606.
[http://dx.doi.org/10.1038/bjc.2013.644] [PMID: 24157830]
[65]
Ravikumar, B.; Vacher, C.; Berger, Z.; Davies, J.E.; Luo, S.; Oroz, L.G.; Scaravilli, F.; Easton, D.F.; Duden, R.; O’Kane, C.J.; Rubinsztein, D.C. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington di-sease. Nat. Genet., 2004, 36(6), 585-595.
[http://dx.doi.org/10.1038/ng1362] [PMID: 15146184]
[66]
Sarkar, S.; Davies, J.E.; Huang, Z.; Tunnacliffe, A.; Rubinsztein, D.C. Trehalose, a novel mTOR-independent autophagy enhancer, accele-rates the clearance of mutant huntingtin and α-synuclein. J. Biol. Chem., 2007, 282(8), 5641-5652.
[http://dx.doi.org/10.1074/jbc.M609532200] [PMID: 17182613]
[67]
Cao, C.; Subhawong, T.; Albert, J.M.; Kim, K.W.; Geng, L.; Sekhar, K.R.; Gi, Y.J.; Lu, B. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res., 2006, 66(20), 10040-10047.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0802] [PMID: 17047067]
[68]
Albert, J.M.; Kim, K.W.; Cao, C.; Lu, B. Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol. Cancer Ther., 2006, 5(5), 1183-1189.
[http://dx.doi.org/10.1158/1535-7163.MCT-05-0400] [PMID: 16731750]
[69]
Nam, H.Y.; Han, M.W.; Chang, H.W.; Lee, Y.S.; Lee, M.; Lee, H.J.; Lee, B.W.; Lee, H.J.; Lee, K.E.; Jung, M.K.; Jeon, H.; Choi, S.H.; Park, N.H.; Kim, S.Y.; Kim, S.W. Radioresistant cancer cells can be conditioned to enter senescence by mTOR inhibition. Cancer Res., 2013, 73(14), 4267-4277.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3516] [PMID: 23722550]
[70]
Empl, M.T.; Cai, H.; Wang, S.; Junginger, J.; Kostka, T.; Hewicker-Trautwein, M.; Brown, K.; Gescher, A.J.; Steinberg, P. Effects of a grapevine shoot extract containing resveratrol and resveratrol oligomers on intestinal adenoma development in mice: In vitro and in vivo studies. Mol. Nutr. Food Res., 2018, 62(2), 1700450.
[http://dx.doi.org/10.1002/mnfr.201700450] [PMID: 29125219]
[71]
Chai, R.; Fu, H.; Zheng, Z.; Liu, T.; Ji, S.; Li, G. Resveratrol inhibits proliferation and migration through SIRT1 mediated post translational modification of PI3K/AKT signaling in hepatocellular carcinoma cells. Mol. Med. Rep., 2017, 16(6), 8037-8044.
[http://dx.doi.org/10.3892/mmr.2017.7612] [PMID: 28983625]
[72]
Wang, J.; Li, J.; Cao, N.; Li, Z.; Han, J.; Li, L. Resveratrol, an activator of SIRT1, induces protective autophagy in non-small-cell lung cancer via inhibiting Akt/mTOR and activating p38-MAPK. OncoTargets Ther., 2018, 11, 7777-7786.
[http://dx.doi.org/10.2147/OTT.S159095] [PMID: 30464525]
[73]
Wu, L.; Yan, B. Discovery of small molecules that target autophagy for cancer treatment. Curr. Med. Chem., 2011, 18(12), 1866-1873.
[http://dx.doi.org/10.2174/092986711795496773] [PMID: 21466466]
[74]
Memmott, R.M.; Mercado, J.R.; Maier, C.R.; Kawabata, S.; Fox, S.D.; Dennis, P.A. Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev. Res. (Phila.), 2010, 3(9), 1066-1076.
[http://dx.doi.org/10.1158/1940-6207.CAPR-10-0055] [PMID: 20810672]
[75]
Ben Sahra, I.; Laurent, K.; Giuliano, S.; Larbret, F.; Ponzio, G.; Gounon, P.; Le Marchand-Brustel, Y.; Giorgetti-Peraldi, S.; Cormont, M.; Bertolotto, C.; Deckert, M.; Auberger, P.; Tanti, J.F.; Bost, F. Targeting cancer cell metabolism: The combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res., 2010, 70(6), 2465-2475.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-2782] [PMID: 20215500]
[76]
Candido, S.; Abrams, S.L.; Steelman, L.; Lertpiriyapong, K.; Martelli, A.M.; Cocco, L.; Ratti, S.; Follo, M.Y.; Murata, R.M.; Rosalen, P.L.; Lombardi, P.; Montalto, G.; Cervello, M.; Gizak, A.; Rakus, D.; Suh, P.G.; Libra, M.; McCubrey, J.A. Metformin influences drug sensitivi-ty in pancreatic cancer cells. Adv. Biol. Regul., 2018, 68, 13-30.
[http://dx.doi.org/10.1016/j.jbior.2018.02.002] [PMID: 29482945]
[77]
Bischoff, P.; Josset, E.; Dumont, F.J. Novel pharmacological modulators of autophagy and therapeutic prospects. Expert Opin. Ther. Pat., 2012, 22(9), 1053-1079.
[http://dx.doi.org/10.1517/13543776.2012.715148] [PMID: 22860892]
[78]
Wu, Y.T.; Tan, H.L.; Shui, G.; Bauvy, C.; Huang, Q.; Wenk, M.R.; Ong, C.N.; Codogno, P.; Shen, H.M. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J. Biol. Chem., 2010, 285(14), 10850-10861.
[http://dx.doi.org/10.1074/jbc.M109.080796] [PMID: 20123989]
[79]
Mackenzie, A.H. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am. J. Med., 1983, 75(1A), 40-45.
[http://dx.doi.org/10.1016/0002-9343(83)91269-X] [PMID: 6869410]
[80]
Livesey, K.M.; Tang, D.; Zeh, H.J.; Lotze, M.T. Autophagy inhibition in combination cancer treatment. Curr. Opin. Investig. Drugs, 2009, 10(12), 1269-1279.
[PMID: 19943199]
[81]
Shoemaker, J.P. Fifty-five percent complete remission of mammary carcinoma in mice with 5-fluorouracil and chloroquine. Cancer Res., 1978, 38(9), 2700-2702.
[PMID: 679173]
[82]
Mirzoeva, O.K.; Hann, B.; Hom, Y.K.; Debnath, J.; Aftab, D.; Shokat, K.; Korn, W.M. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. J. Mol. Med. (Berl.), 2011, 89(9), 877-889.
[http://dx.doi.org/10.1007/s00109-011-0774-y] [PMID: 21678117]
[83]
McAfee, Q.; Zhang, Z.; Samanta, A.; Levi, S.M.; Ma, X.H.; Piao, S.; Lynch, J.P.; Uehara, T.; Sepulveda, A.R.; Davis, L.E.; Winkler, J.D.; Amaravadi, R.K. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy de-ficiency. Proc. Natl. Acad. Sci. USA, 2012, 109(21), 8253-8258.
[http://dx.doi.org/10.1073/pnas.1118193109] [PMID: 22566612]
[84]
Klionsky, D.J.; Elazar, Z.; Seglen, P.O.; Rubinsztein, D.C. Does bafilomycin A1 block the fusion of autophagosomes with lysosomes? Autophagy, 2008, 4(7), 849-850.
[http://dx.doi.org/10.4161/auto.6845] [PMID: 18758232]
[85]
Wang, K.; Zhang, Z.; Wang, M.; Cao, X.; Qi, J.; Wang, D.; Gong, A.; Zhu, H. Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Drug Des. Devel. Ther., 2019, 13, 2135-2144.
[http://dx.doi.org/10.2147/DDDT.S199459] [PMID: 31456633]
[86]
Xie, Y.; Hou, W.; Song, X.; Yu, Y.; Huang, J.; Sun, X.; Kang, R.; Tang, D. Ferroptosis: Process and function. Cell Death Differ., 2016, 23(3), 369-379.
[http://dx.doi.org/10.1038/cdd.2015.158] [PMID: 26794443]
[87]
Hou, W.; Xie, Y.; Song, X.; Sun, X.; Lotze, M.T.; Zeh, H.J., III; Kang, R.; Tang, D. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy, 2016, 12(8), 1425-1428.
[http://dx.doi.org/10.1080/15548627.2016.1187366] [PMID: 27245739]
[88]
Zhu, S.; Zhang, Q.; Sun, X.; Zeh, H.J., III; Lotze, M.T.; Kang, R.; Tang, D. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res., 2017, 77(8), 2064-2077.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-1979] [PMID: 28130223]
[89]
Chen, G.; Guo, G.; Zhou, X.; Chen, H. Potential mechanism of ferroptosis in pancreatic cancer. Oncol. Lett., 2020, 19(1), 579-587.
[PMID: 31897173]

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