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Anti-Cancer Agents in Medicinal Chemistry

Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Repurposing of Alexidine Dihydrochloride as an Apoptosis Initiator and Cell Cycle Inhibitor in Human Pancreatic Cancer

Author(s): Ezgi Kasikciorcid of author, Esra Aydemirorcid of author, Bekir M. Yogurtcu, Fikrettin Sahinorcid of author and Omer F. Bayrak*

Volume 20, Issue 16, 2020

Page: [1956 - 1965] Pages: 10

DOI: 10.2174/1871520620666200508085439

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Abstract

Background: Highly aggressive and resistant to chemotherapy, pancreatic cancers are the fourth leading cause of cancer-related deaths in the western world. The absence of effective chemotherapeutics is leading researchers to develop novel drugs or repurpose existing chemicals. Alexidine Dihydrochloride (AD), an orally bioavailable bis-biguanide compound, is an apoptosis stimulating reagent. It induces mitochondrial damage by inhibiting a mitochondrial-specific protein tyrosine phosphatase, PTPMT1. The aim of this study was to test AD as a novel compound to induce apoptosis in a human pancreatic adenocarcinoma cell lines, Panc-1, MIA PaCa-2, AsPC-1, and Psn-1.

Methods: After the IC50 value of the AD was determined by cytotoxicity assay, apoptosis was observed by a variety of methods, including the detection of early apoptosis marker Annexin V and the proteomic profile screening by apoptosis array. Multicaspase and mitochondrial depolarization were measured, and changes in the cell cycle were analyzed.

Results: AD is found to initiate apoptosis by activating the intrinsic pathway and inhibit the cell cycle in pancreatic cancer cell lines.

Conclusion: In conclusion, considering its anti-cancer properties and bioavailability, Alexidine dihydrochloride can be considered as a potential candidate against pancreatic adenocarcinomas.

Keywords: Cancer, pancreatic adenocarcinoma, alexidine dihydrochloride, chemotherapy, apoptosis, cell cycle.

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Graphical Abstract

Graphical abstract illustrating key findings of the study

[1]
Sohn, T.A.; Yeo, C.J.; Cameron, J.L.; Koniaris, L.; Kaushal, S.; Abrams, R.A.; Sauter, P.K.; Coleman, J.; Hruban, R.H.; Lillemoe, K.D. Resected adenocarcinoma of the pancreas-616 patients: Results, outcomes, and prognostic indicators. J. Gastrointest. Surg., 2000, 4(6), 567-579.
[http://dx.doi.org/10.1016/S1091-255X(00)80105-5 ] [PMID: 11307091]
[2]
Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. Pancreatic cancer stem cells and EMT in drug resistance and metastasis. Minerva Chir., 2009, 64(5), 489-500.
[PMID: 19859039]
[3]
Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J.L. Pancreatic cancer. Lancet, 2004, 363(9414), 1049-1057.
[http://dx.doi.org/10.1016/S0140-6736(04)15841-8 ] [PMID: 15051286]
[4]
Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer, 2005, 5(4), 275-284.
[http://dx.doi.org/10.1038/nrc1590 ] [PMID: 15803154]
[5]
Neoptolemos, J.P.; Stocken, D.D.; Bassi, C.; Ghaneh, P.; Cunningham, D.; Goldstein, D.; Padbury, R.; Moore, M.J.; Gallinger, S.; Mariette, C.; Wente, M.N.; Izbicki, J.R.; Friess, H.; Lerch, M.M.; Dervenis, C.; Oláh, A.; Butturini, G.; Doi, R.; Lind, P.A.; Smith, D.; Valle, J.W.; Palmer, D.H.; Buckels, J.A.; Thompson, J.; McKay, C.J.; Rawcliffe, C.L.; Büchler, M.W.; Canc, E.S.G.P. European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA, 2010, 304(10), 1073-1081.
[http://dx.doi.org/10.1001/jama.2010.1275 ] [PMID: 20823433]
[6]
Regine, W.F.; Winter, K.A.; Abrams, R.; Safran, H.; Hoffman, J.P.; Konski, A.; Benson, A.B.; Macdonald, J.S.; Rich, T.A.; Willett, C.G. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann. Surg. Oncol., 2011, 18(5), 1319-1326.
[http://dx.doi.org/10.1245/s10434-011-1630-6 ] [PMID: 21499862]
[7]
Gjermo, P.; Rölla, G.; Årskaug, L. Effect on dental plaque formation and some in vitro properties of 12 bis-biguanides. J. Periodontal Res. Suppl., 1973, 12(s12), 81-92.
[http://dx.doi.org/10.1111/j.1600-0765.1973.tb02169.x ] [PMID: 4269606]
[8]
McDonnell, G.; Russell, A.D. Antiseptics and disinfectants: Activity, action, and resistance. Clin. Microbiol. Rev., 1999, 12(1), 147-179.
[http://dx.doi.org/10.1128/CMR.12.1.147] [PMID: 9880479]
[9]
Myron, L. Tooth cleaning preparation. Canada Patent CA931507A,, 1973.
[10]
Roberts, W.R.; Addy, M. Comparison of the in vivo and in vitro antibacterial properties of antiseptic mouthrinses containing chlorhexidine, alexidine, cetyl pyridinium chloride and hexetidine. Relevance to mode of action. J. Clin. Periodontol., 1981, 8(4), 295-310.
[http://dx.doi.org/10.1111/j.1600-051X.1981.tb02040.x ] [PMID: 6947993]
[11]
Formicola, A.J.; Deasy, M.J.; Graessle, O.E.; Johnson, D.H.; Howe, E.E. The effect of an alexidine mouthwash on plaque and gingivitis. J. Periodontol., 1978, 49(3), 145-147.
[http://dx.doi.org/10.1902/jop.1978.49.3.145 ] [PMID: 381628]
[12]
Yip, K.W.; Ito, E.; Mao, X.; Au, P.Y.; Hedley, D.W.; Mocanu, J.D.; Bastianutto, C.; Schimmer, A.; Liu, F.F. Potential use of alexidine dihydrochloride as an apoptosis-promoting anticancer agent. Mol. Cancer Ther., 2006, 5(9), 2234-2240.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0134 ] [PMID: 16985057]
[13]
Pagliarini, D.J.; Worby, C.A.; Dixon, J.E. A PTEN-like phosphatase with a novel substrate specificity. J. Biol. Chem., 2004, 279(37), 38590-38596.
[http://dx.doi.org/10.1074/jbc.M404959200 ] [PMID: 15247229]
[14]
Osman, C.; Voelker, D.R.; Langer, T. Making heads or tails of phospholipids in mitochondria. J. Cell Biol., 2011, 192(1), 7-16.
[http://dx.doi.org/10.1083/jcb.201006159 ] [PMID: 21220505]
[15]
Doughty-Shenton, D.; Joseph, J.D.; Zhang, J.; Pagliarini, D.J.; Kim, Y.; Lu, D.; Dixon, J.E.; Casey, P.J. Pharmacological targeting of the mitochondrial phosphatase PTPMT1. J. Pharmacol. Exp. Ther., 2010, 333(2), 584-592.
[http://dx.doi.org/10.1124/jpet.109.163329 ] [PMID: 20167843]
[16]
El-Kouhen, K.; Tremblay, M.L. PTPMT1: Connecting cardiolipin biosynthesis to mitochondrial function. Cell Metab., 2011, 13(6), 615-617.
[http://dx.doi.org/10.1016/j.cmet.2011.05.005 ] [PMID: 21641541]
[17]
Zhang, J.; Guan, Z.; Murphy, A.N.; Wiley, S.E.; Perkins, G.A.; Worby, C.A.; Engel, J.L.; Heacock, P.; Nguyen, O.K.; Wang, J.H.; Raetz, C.R.H.; Dowhan, W.; Dixon, J.E. Mitochondrial phosphatase PTPMT1 is essential for cardiolipin biosynthesis. Cell Metab., 2011, 13(6), 690-700.
[http://dx.doi.org/10.1016/j.cmet.2011.04.007 ] [PMID: 21641550]
[18]
Pagliarini, D.J.; Wiley, S.E.; Kimple, M.E.; Dixon, J.R.; Kelly, P.; Worby, C.A.; Casey, P.J.; Dixon, J.E. Involvement of a mitochondrial phosphatase in the regulation of ATP production and insulin secretion in pancreatic beta cells. Mol. Cell, 2005, 19(2), 197-207.
[http://dx.doi.org/10.1016/j.molcel.2005.06.008 ] [PMID: 16039589]
[19]
Niemi, N.M.; Sacoman, J.L.; Westrate, L.M.; Gaither, L.A.; Lanning, N.J.; Martin, K.R.; MacKeigan, J.P. The pseudophosphatase MK-STYX physically and genetically interacts with the mitochondrial phosphatase PTPMT1. PLoS One, 2014, 9(4),e93896.
[http://dx.doi.org/10.1371/journal.pone.0093896] [PMID: 24709986]
[20]
Nath, A.K.; Ryu, J.H.; Jin, Y.N.; Roberts, L.D.; Dejam, A.; Gerszten, R.E.; Peterson, R.T. PTPMT1 inhibition lowers glucose through succinate dehydrogenase phosphorylation. Cell Rep., 2015, 10(5), 694-701.
[http://dx.doi.org/10.1016/j.celrep.2015.01.010 ] [PMID: 25660020]
[21]
Niemi, N.M.; Lanning, N.J.; Westrate, L.M.; MacKeigan, J.P. Downregulation of the mitochondrial phosphatase PTPMT1 is sufficient to promote cancer cell death. PLoS One, 2013, 8(1),e53803.
[http://dx.doi.org/10.1371/journal.pone.0053803] [PMID: 23326511]
[22]
Chicco, A.J.; Sparagna, G.C. Role of cardiolipin alterations in mitochondrial dysfunction and disease. Am. J. Physiol. Cell Physiol., 2007, 292(1), C33-C44.
[http://dx.doi.org/10.1152/ajpcell.00243.2006 ] [PMID: 16899548]
[23]
Ruiz-Linares, M.; Ferrer-Luque, C.M.; Arias-Moliz, T.; de Castro, P.; Aguado, B.; Baca, P. Antimicrobial activity of alexidine, chlorhexidine and cetrimide against Streptococcus mutans biofilm. Ann. Clin. Microbiol. Antimicrob., 2014, 13(1), 41.
[http://dx.doi.org/10.1186/s12941-014-0041-5 ] [PMID: 25139679]
[24]
Zhu, X.; Gao, J.; Ng, P.Y.; Qin, A.; Steer, J.H.; Pavlos, N.J.; Zheng, M.H.; Dong, Y.; Cheng, T.S. Alexidine dihydrochloride attenuates osteoclast formation and bone resorption and protects against LPS-induced osteolysis. J. Bone Miner. Res., 2016, 31(3), 560-572.
[http://dx.doi.org/10.1002/jbmr.2710] [PMID: 26363136]
[25]
Yuki, K.; Miyauchi, T.; Kakinuma, Y.; Murakoshi, N.; Suzuki, T.; Hayashi, J.; Goto, K.; Yamaguchi, I. Mitochondrial dysfunction increases expression of endothelin-1 and induces apoptosis through caspase-3 activation in rat cardiomyocytes in vitro. J. Cardiovasc. Pharmacol., 2000, 36(5)(Suppl. 1), S205-S208.
[http://dx.doi.org/10.1097/00005344-200036051-00062 ] [PMID: 11078378]
[26]
Chandra, D.; Choy, G.; Deng, X.; Bhatia, B.; Daniel, P.; Tang, D.G. Association of active caspase 8 with the mitochondrial membrane during apoptosis: Potential roles in cleaving BAP31 and caspase 3 and mediating mitochondrion-endoplasmic reticulum cross talk in etoposide-induced cell death. Mol. Cell. Biol., 2004, 24(15), 6592-6607.
[http://dx.doi.org/10.1128/MCB.24.15.6592-6607.2004 ] [PMID: 15254227]
[27]
Chen, Q.; Gong, B.; Almasan, A. Distinct stages of cytochrome c release from mitochondria: Evidence for a feedback amplification loop linking caspase activation to mitochondrial dysfunction in genotoxic stress induced apoptosis. Cell Death Differ., 2000, 7(2), 227-233.
[http://dx.doi.org/10.1038/sj.cdd.4400629 ] [PMID: 10713737]
[28]
Bhanot, U.; Heydrich, R.; Möller, P.; Hasel, C. Survivin expression in pancreatic intraepithelial neoplasia (PanIN): Steady increase along the developmental stages of pancreatic ductal adenocarcinoma. Am. J. Surg. Pathol., 2006, 30(6), 754-759.
[http://dx.doi.org/10.1097/00000478-200606000-00013 ] [PMID: 16723855]
[29]
Lopes, R.B.; Gangeswaran, R.; McNeish, I.A.; Wang, Y.; Lemoine, N.R. Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int. J. Cancer, 2007, 120(11), 2344-2352.
[http://dx.doi.org/10.1002/ijc.22554 ] [PMID: 17311258]
[30]
König, J.; Hartel, M.; Nies, A.T.; Martignoni, M.E.; Guo, J.; Büchler, M.W.; Friess, H.; Keppler, D. Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int. J. Cancer, 2005, 115(3), 359-367.
[http://dx.doi.org/10.1002/ijc.20831 ] [PMID: 15688370]
[31]
Bunz, F.; Hwang, P.M.; Torrance, C.; Waldman, T.; Zhang, Y.; Dillehay, L.; Williams, J.; Lengauer, C.; Kinzler, K.W.; Vogelstein, B. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J. Clin. Invest., 1999, 104(3), 263-269.
[http://dx.doi.org/10.1172/JCI6863 ] [PMID: 10430607]
[32]
Flatt, P.M.; Tang, L.J.; Scatena, C.D.; Szak, S.T.; Pietenpol, J.A. p53 regulation of G2 checkpoint is retinoblastoma protein dependent. Mol. Cell. Biol., 2000, 20(12), 4210-4223.
[http://dx.doi.org/10.1128/MCB.20.12.4210-4223.2000 ] [PMID: 10825186]
[33]
Tyagi, A.K.; Singh, R.P.; Agarwal, C.; Chan, D.C.; Agarwal, R. Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res., 2002, 8(11), 3512-3519.
[34]
Wang, C.; Niederstrasser, H.; Douglas, P.M.; Lin, R.; Jaramillo, J.; Li, Y.; Oswald, N.W.; Zhou, A.; McMillan, E.A.; Mendiratta, S.; Wang, Z.; Zhao, T.; Lin, Z.; Luo, M.; Huang, G.; Brekken, R.A.; Posner, B.A.; MacMillan, J.B.; Gao, J.; White, M.A. Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan. Nat. Commun., 2017, 8(1), 2270.
[http://dx.doi.org/10.1038/s41467-017-02332-3 ] [PMID: 29273768]

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