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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Successful Pre-Clinical Management of Irinotecan-Debilitated Animals: A Protein- Based Accessory Phytomedicine

Author(s): Gisele F. P. Rangel, Márcio V. Ramos*, Luana D. do Carmo, Liviane M. A. Rabelo, Alfredo A. V. Silva, Tamiris F. G. de Sousa, Roberto C. P. Lima Júnior, Deysi V. T. Wong, Renata F. C. Leitão, Pedro J. C. Magalhães, Brandon F. Sousa, Marisa J. S. Frederico and Nylane M. N. Alencar*

Volume 22, Issue 18, 2022

Published on: 04 August, 2022

Page: [3163 - 3171] Pages: 9

DOI: 10.2174/1871520622666220610115617

Price: $65

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Abstract

Background: Calotropis procera is a laticiferous plant (Apocynaceae) found in tropical regions all over the world. The ultrastructural characteristics of laticifers, their restricted distribution among different taxonomic groups, and in some species in each clade, as peptidases from latex, make them very attractive for biological analysis.

Objective: The study aims to investigate the effects of LP-PII-IAA (laticifer protein (LP) sub-fraction II (PII) of C. procera presenting an iodoacetamide-inhibited cysteine proteinase activity) on irinotecan-induced intestinal mucositis, a serious adverse effect of this medicine for the treatment of cancer.

Methods: LP-PII-IAA is composed of closely related isoforms (90%) of peptidases derived from catalysis and an osmotin protein (5%). Animals receiving co-administration of LP-PII-IAA presented a significant decrease in mortality, absence of diarrhea, histological preservation, and normalization of intestinal functions.

Results: Clinical homeostasis was accompanied by a reduction in MPO activity and declined levels of IL-1β, IL-6 and KC, while the IL-10 level increased in LP-PII-IAA-treated animals. COX-2 and NF-kB immunostaining was reduced and the levels of oxidative markers (GSH, MDA) were normalized in animals that received LP-PII-IAA.

Conclusion: We suggest that peptidases from the latex of Calotropis procera were instrumental in the suppression of the adverse clinical and physiological effects of irinotecan.

Keywords: Calotropis procera, chemotherapy, homeostasis, latex, side-effect, diarrhea.

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[1]
Gibson, R.J.; Bowen, J.M.; Inglis, M.R.; Cummins, A.G.; Keefe, D.M. Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer. J. Gastroenterol. Hepatol., 2003, 18(9), 1095-1100.
[http://dx.doi.org/10.1046/j.1440-1746.2003.03136.x] [PMID: 12911669]
[2]
Boeing, T.; Gois, M.B.; de Souza, P.; Somensi, L.B.; Sant Ana, D.M.G.; da Silva, L.M. Irinotecan-induced intestinal mucositis in mice: A histopathological study. Cancer Chemother. Pharmacol., 2021, 87(3), 327-336.
[http://dx.doi.org/10.1007/s00280-020-04186-x] [PMID: 33130913]
[3]
Kwon, Y. Mechanism-based management for mucositis: Option for treating side effects without compromising the efficacy of cancer ther-apy. OncoTargets Ther., 2016, 9, 2007-2016.
[http://dx.doi.org/10.2147/OTT.S96899] [PMID: 27103826]
[4]
Assy, N.; Basher, W.; Chetver, L.; Shnaider, J.; Zidan, J. First-line treatment with capecitabine combined with irinotecan in patients with advanced colorectal carcinoma: A phase II study. J. Clin. Gastroenterol., 2012, 46(4), e27-e30.
[http://dx.doi.org/10.1097/MCG.0b013e3182470f09] [PMID: 22392022]
[5]
Ribeiro, R.A.; Wanderley, C.W.; Wong, D.V.; Mota, J.M.; Leite, C.A.; Souza, M.H.; Cunha, F.Q.; Lima-Júnior, R.C. Irinotecan- and 5-fluorouracil-induced intestinal mucositis: Insights into pathogenesis and therapeutic perspectives. Cancer Chemother. Pharmacol., 2016, 78(5), 881-893.
[http://dx.doi.org/10.1007/s00280-016-3139-y] [PMID: 27590709]
[6]
Wong, D.V.; Lima-Júnior, R.C.; Carvalho, C.B.; Borges, V.F.; Wanderley, C.W.; Bem, A.X.; Leite, C.A.; Teixeira, M.A.; Batista, G.L.; Sil-va, R.L.; Cunha, T.M.; Brito, G.A.; Almeida, P.R.; Cunha, F.Q.; Ribeiro, R.A. The adaptor protein Myd88 is a key signaling molecule in the pathogenesis of irinotecan-induced intestinal mucositis. PLoS One, 2015, 10(10), e0139985.
[http://dx.doi.org/10.1371/journal.pone.0139985] [PMID: 26440613]
[7]
Wardill, H.R.; Bowen, J.M.; Van Sebille, Y.Z.; Secombe, K.R.; Coller, J.K.; Ball, I.A.; Logan, R.M.; Gibson, R.J. TLR4-dependent claudin-1 internalization and secretagogue-mediated chloride secretion regulate irinotecan-induced diarrhea. Mol. Cancer Ther., 2016, 15(11), 2767-2779.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0330] [PMID: 27550942]
[8]
Lima-Júnior, R.C.P.; Freitas, H.C.; Wong, D.V.T.; Wanderley, C.W.S.; Nunes, L.G.; Leite, L.L.; Miranda, S.P.; Souza, M.H.L.P.; Brito, G.A.C.; Magalhães, P.J.C.; Teixeira, M.M.; Cunha, F.Q.; Ribeiro, R.A. Targeted inhibition of IL-18 attenuates irinotecan-induced intestinal mucositis in mice. Br. J. Pharmacol., 2014, 171(9), 2335-2350.
[http://dx.doi.org/10.1111/bph.12584] [PMID: 24428790]
[9]
Arifa, R.D.; Madeira, M.F.; de Paula, T.P.; Lima, R.L.; Tavares, L.D.; Menezes-Garcia, Z.; Fagundes, C.T.; Rachid, M.A.; Ryffel, B.; Zam-boni, D.S.; Teixeira, M.M.; Souza, D.G. Inflammasome activation is reactive oxygen species dependent and mediates irinotecan-induced mucositis through IL-1β and IL-18 in mice. Am. J. Pathol., 2014, 184(7), 2023-2034.
[http://dx.doi.org/10.1016/j.ajpath.2014.03.012] [PMID: 24952429]
[10]
Guabiraba, R.; Besnard, A.G.; Menezes, G.B.; Secher, T.; Jabir, M.S.; Amaral, S.S.; Braun, H.; Lima-Junior, R.C.P.; Ribeiro, R.A.; Cunha, F.Q.; Teixeira, M.M.; Beyaert, R.; Graham, G.J.; Liew, F.Y. IL-33 targeting attenuates intestinal mucositis and enhances effective tumor chemotherapy in mice. Mucosal Immunol., 2014, 7(5), 1079-1093.
[http://dx.doi.org/10.1038/mi.2013.124] [PMID: 24424522]
[11]
Wardill, H.R.; Gibson, R.J.; Van Sebille, Y.Z.; Secombe, K.R.; Coller, J.K.; White, I.A.; Manavis, J.; Hutchinson, M.R.; Staikopoulos, V.; Logan, R.M.; Bowen, J.M. Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mecha-nisms. Mol. Cancer Ther., 2016, 15(6), 1376-1386.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0990] [PMID: 27197307]
[12]
Elad, S.; Cheng, K.K.F.; Lalla, R.V.; Yarom, N.; Hong, C.; Logan, R.M.; Bowen, J.; Gibson, R.; Saunders, D.P.; Zadik, Y.; Ariyawardana, A.; Correa, M.E.; Ranna, V.; Bossi, P.; Arany, P.; Al-Azri, A.R.; Blijlevens, N.; Hovan, A.; Fregnani, E.; Fulton, J.; Gueiros, L.A.; Rouleau, T.; Coller, J.K.; Al-Dasooqi, N.; Wardill, H.; Ameringer, S.; Antunes, H.S.; Bateman, E.H.; Bektas, K.; Bensadoun, R-J.; Ten Bohmer, K.; Brito-Dellan, N.; Castillo, D.; Chiang, K.; de Mooij, C.; Eilers, J.; Epstein, J.; Galiti, D.; Fall-Dickson, J.M.; Gobbo, M.; Issa Hazboun, H.; Jensen, S.B.; Johansen, J.; Joy, J.; Joy, K.; Kandwal, A.; Kataoka, T.; Keefe, D.; Loprinzi, C.L.; Lubart, R.; Skripnik Lucas, A.; Majorana, A.; Mayo, B.; de Mooij, C.; Mori, T.; Nair, R.G.; Nasr, N.; Nicolatou-Galitis, O.; Ottaviani, G.; Migliorati, C.; Pentenero, M.; Porcello, L.; Peterson, D.; Potting, C.; Raber-Durlacher, J.; van Sebille, Y.Z.A.; Soga, Y.; Sonis, S.; Stringer, A.M.; Thorpe, D.; Tilly, V.; Tissing, W.; Toro, J.J.; Treister, N.S.; Vaddi, A.; Weikel, D.; van de Wetering, M.; Zur, E. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer, 2020, 126(19), 4423-4431.
[http://dx.doi.org/10.1002/cncr.33100] [PMID: 32786044]
[13]
Ramos, M.V.; Demarco, D.; da Costa Souza, I.C.; de Freitas, C.D.T. Laticifers, latex, and their role in plant defense. Trends Plant Sci., 2019, 24(6), 553-567.
[http://dx.doi.org/10.1016/j.tplants.2019.03.006] [PMID: 30979674]
[14]
Freitas, A.P.F.; Bitencourt, F.S.; Brito, G.A.C.; de Alencar, N.M.; Ribeiro, R.A.; Lima-Júnior, R.C.P.; Ramos, M.V.; Vale, M.L. Protein fraction of Calotropis procera latex protects against 5-fluorouracil-induced oral mucositis associated with downregulation of pivotal pro-inflammatory mediators. Naunyn Schmiedebergs Arch. Pharmacol., 2012, 385(10), 981-990.
[http://dx.doi.org/10.1007/s00210-012-0778-3] [PMID: 22797601]
[15]
de Alencar, N.M.; da Silveira Bitencourt, F.; de Figueiredo, I.S.; Luz, P.B.; Lima-Júnior, R.C.P.; Aragão, K.S.; Magalhães, P.J.C.; de Castro Brito, G.A.; Ribeiro, R.A.; de Freitas, A.P.; Ramos, M.V. Side-Effects of irinotecan (CPT-11), the clinically used drug for colon cancer therapy, are eliminated in experimental animals treated with latex proteins from Calotropis procera (Apocynaceae). Phytother. Res., 2017, 31(2), 312-320.
[http://dx.doi.org/10.1002/ptr.5752] [PMID: 27910140]
[16]
Ramos, M.V.; Oliveira, J.S.; Figueiredo, J.G.; Figueiredo, I.S.; Kumar, V.L.; Bitencourt, F.S.; Cunha, F.Q.; Oliveira, R.S.B.; Bomfim, L.R.; Vitor Lima-Filho, J.; Alencar, N.M. Involvement of NO in the inhibitory effect of Calotropis procera latex protein fractions on leukocyte rolling, adhesion and infiltration in rat peritonitis model. J. Ethnopharmacol., 2009, 125(3), 387-392.
[http://dx.doi.org/10.1016/j.jep.2009.07.030] [PMID: 19647058]
[17]
Ramos, M.V.; Araújo, E.S.; Jucá, T.L.; Monteiro-Moreira, A.C.O.; Vasconcelos, I.M.; Moreira, R.A.; Viana, C.A.; Beltramini, L.M.; Perei-ra, D.A.; Moreno, F.B. New insights into the complex mixture of latex cysteine peptidases in Calotropis procera. Int. J. Biol. Macromol., 2013, 58, 211-219.
[http://dx.doi.org/10.1016/j.ijbiomac.2013.04.001] [PMID: 23583491]
[18]
Freitas, C.D.T.; Silva, R.O.; Ramos, M.V.; Porfírio, C.T.M.N.; Farias, D.F.; Sousa, J.S.; Oliveira, J.P.B.; Souza, P.F.N.; Dias, L.P.; Grangeiro, T.B. Identification, characterization, and antifungal activity of cysteine peptidases from Calotropis procera latex. Phytochemistry, 2020, 169112163.
[http://dx.doi.org/10.1016/j.phytochem.2019.112163] [PMID: 31605904]
[19]
de Freitas, C.D.; Lopes, J.L.S.; Beltramini, L.M.; de Oliveira, R.S.; Oliveira, J.T.A.; Ramos, M.V. Osmotin from Calotropis procera latex: New insights into structure and antifungal properties. Biochim. Biophys. Acta, 2011, 1808(10), 2501-2507.
[http://dx.doi.org/10.1016/j.bbamem.2011.07.014] [PMID: 21798235]
[20]
Ikuno, N.; Soda, H.; Watanabe, M.; Oka, M. Irinotecan (CPT-11) and characteristic mucosal changes in the mouse ileum and cecum. J. Natl. Cancer Inst., 1995, 87(24), 1876-1883.
[http://dx.doi.org/10.1093/jnci/87.24.1876] [PMID: 7494232]
[21]
Melo, M.L.P.; Brito, G.A.; Soares, R.C.; Carvalho, S.B.; Silva, J.V.; Soares, P.M.; Vale, M.L.; Souza, M.H.L.P.; Cunha, F.Q.; Ribeiro, R.A. Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: Effect of pentoxifyl-line and thalidomide. Cancer Chemother. Pharmacol., 2008, 61(5), 775-784.
[http://dx.doi.org/10.1007/s00280-007-0534-4] [PMID: 17624531]
[22]
Kurita, A.; Kado, S.; Kaneda, N.; Onoue, M.; Hashimoto, S.; Yokokura, T. Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats. Cancer Chemother. Pharmacol., 2000, 46(3), 211-220.
[http://dx.doi.org/10.1007/s002800000151] [PMID: 11021738]
[23]
Araújo, P.V.; Clemente, C.M.; da Graça, J.R.; Rola, F.H.; de Oliveira, R.B.; dos Santos, A.A.; Magalhães, P.J.C. Inhibitory effect of sildena-fil on rat duodenal contractility in vitro: Putative cGMP involvement. Clin. Exp. Pharmacol. Physiol., 2005, 32(3), 191-195.
[http://dx.doi.org/10.1111/j.1440-1681.2005.04170.x] [PMID: 15743402]
[24]
Costa, D.V.S.; Costa, D.V.S.; Sousa, C.N.S.; Silva, A.M.H.P.; Medeiros, I.S.; Martins, D.S.; Martins, C.S.; Pequeno, A.L.V.; Lima-Júnior, R.C.P.; Soares, P.M.G.; Vasconcelos, S.M.M.; Brito, G.A.C.; Souza, E.P. The alpha-lipoic acid improves survival and prevents irinotecan-induced inflammation and intestinal dysmotility in mice. Pharmaceuticals (Basel), 2020, 13(11), 361.
[http://dx.doi.org/10.3390/ph13110361] [PMID: 33152996]
[25]
Sedlak, J.; Lindsay, R.H. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal. Biochem., 1968, 25(1), 192-205.
[http://dx.doi.org/10.1016/0003-2697(68)90092-4] [PMID: 4973948]
[26]
Draper, H.H.; Hadley, M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol., 1990, 186, 421-431.
[http://dx.doi.org/10.1016/0076-6879(90)86135-I] [PMID: 2233309]
[27]
Kumar, V.L.; Roy, S.; Sehgal, R.; Padhy, B.M. A comparative study on the efficacy of rofecoxib in monoarticular arthritis induced by latex of Calotropis procera and Freund’s complete adjuvant. Inflammopharmacology, 2006, 14(1-2), 17-21.
[http://dx.doi.org/10.1007/s10787-006-1512-x] [PMID: 16835708]
[28]
Silva, A.F.; Sousa, J.S.; Cunha, P.L.; Lima-Filho, J.V.; Alencar, N.M.N.; Freitas, C.D.T.; Oliveira, C.L.; Ramos, M.V. Erythrocytes mor-phology and hemorheology in severe bacterial infection. Mem. Inst. Oswaldo Cruz, 2019, 114, e190326.
[http://dx.doi.org/10.1590/0074-02760190326] [PMID: 31859703]
[29]
Chaudhary, P.; de Araújo Viana, C.; Ramos, M.V.; Kumar, V.L. Antiedematogenic and antioxidant properties of high molecular weight protein sub-fraction of Calotropis procera latex in rat. J. Basic Clin. Pharm., 2015, 6(2), 69-73.
[http://dx.doi.org/10.4103/0976-0105.152098] [PMID: 25767367]
[30]
Lenfers, B.H.; Loeffler, T.M.; Droege, C.M.; Hausamen, T.U. Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment. Ann. Oncol., 1999, 10(10), 1251-1253.
[http://dx.doi.org/10.1023/A:1008390308416] [PMID: 10586346]
[31]
Hoff, P.M.; Saragiotto, D.F.; Barrios, C.H.; del Giglio, A.; Coutinho, A.K.; Andrade, A.C.; Dutra, C.; Forones, N.M.; Correa, M.; Portella, M.S.; Passos, V.Q.; Chinen, R.N.; van Eyll, B. Randomized phase III trial exploring the use of long-acting release octreotide in the preven-tion of chemotherapy-induced diarrhea in patients with colorectal cancer: The LARCID trial. J. Clin. Oncol., 2014, 32(10), 1006-1011.
[http://dx.doi.org/10.1200/JCO.2013.50.8077] [PMID: 24516038]
[32]
Alencar, N.M.N.; Figueiredo, I.S.T.; Vale, M.R.; Bitencurt, F.S.; Oliveira, J.S.; Ribeiro, R.A.; Ramos, M.V. Anti-inflammatory effect of the latex from Calotropis procera in three different experimental models: Peritonitis, paw edema and hemorrhagic cystitis. Planta Med., 2004, 70(12), 1144-1149.
[http://dx.doi.org/10.1055/s-2004-835842] [PMID: 15643548]
[33]
Bowen, J.; Al-Dasooqi, N.; Bossi, P.; Wardill, H.; Van Sebille, Y.; Al-Azri, A.; Bateman, E.; Correa, M.E.; Raber-Durlacher, J.; Kandwal, A.; Mayo, B.; Nair, R.G.; Stringer, A.; Ten Bohmer, K.; Thorpe, D.; Lalla, R.V.; Sonis, S.; Cheng, K.; Elad, S. The pathogenesis of mucosi-tis: Updated perspectives and emerging targets. Support. Care Cancer, 2019, 27(10), 4023-4033.
[http://dx.doi.org/10.1007/s00520-019-04893-z] [PMID: 31286231]
[34]
Ouyang, M.; Luo, Z.; Zhang, W.; Zhu, D.; Lu, Y.; Wu, J.; Yao, X. Protective effect of curcumin against irinotecan induced intestinal mu-cosal injury via attenuation of NF κB activation, oxidative stress and endoplasmic reticulum stress. Int. J. Oncol., 2019, 54(4), 1376-1386.
[http://dx.doi.org/10.3892/ijo.2019.4714] [PMID: 30968152]
[35]
Thorpe, D.; Butler, R.; Sultani, M.; Vanhoecke, B.; Stringer, A. Irinotecan-induced mucositis is associated with goblet cell dysregulation and neural cell damage in a tumour bearing DA rat model. Pathol. Oncol. Res., 2020, 26(2), 955-965.
[http://dx.doi.org/10.1007/s12253-019-00644-x] [PMID: 30919275]
[36]
Deng, F.; Hu, J.; Yang, X.; Wang, Y.; Lin, Z.; Sun, Q.; Liu, K. Interleukin-10 expands transit-amplifying cells while depleting Lgr5+ stem cells via inhibition of Wnt and notch signaling. Biochem. Biophys. Res. Commun., 2020, 533(4), 1330-1337.
[http://dx.doi.org/10.1016/j.bbrc.2020.10.014] [PMID: 33066957]
[37]
Rtibi, K.; Grami, D.; Selmi, S.; Amri, M.; Sebai, H.; Marzouki, L. Vinblastine, an anticancer drug, causes constipation and oxidative stress as well as others disruptions in intestinal tract in rat. Toxicol. Rep., 2017, 4, 221-225.
[http://dx.doi.org/10.1016/j.toxrep.2017.04.006] [PMID: 28959642]
[38]
Arifa, R.D.N.; Paula, T.P.; Madeira, M.F.M.; Lima, R.L.; Garcia, Z.M.; Ÿvila, T.V.; Pinho, V.; Barcelos, L.S.; Pinheiro, M.V.B.; Ladeira, L.O.; Krambrock, K.; Teixeira, M.M.; Souza, D.G. The reduction of oxidative stress by nanocomposite Fullerol decreases mucositis se-verity and reverts leukopenia induced by Irinotecan. Pharmacol. Res., 2016, 107, 102-110.
[http://dx.doi.org/10.1016/j.phrs.2016.03.004] [PMID: 26987941]
[39]
Boeing, T.; de Souza, P.; Speca, S.; Somensi, L.B.; Mariano, L.N.B.; Cury, B.J.; Ferreira Dos Anjos, M.; Quintão, N.L.M.; Dubuqoy, L.; Desreumax, P.; da Silva, L.M.; de Andrade, S.F. Luteolin prevents irinotecan-induced intestinal mucositis in mice through antioxidant and anti-inflammatory properties. Br. J. Pharmacol., 2020, 177(10), 2393-2408.
[http://dx.doi.org/10.1111/bph.14987] [PMID: 31976547]
[40]
Sousa, B.F.; Silva, A.F.B.D.; Lima-Filho, J.V.; Agostinho, A.G.; Oliveira, D.N.; de Alencar, N.M.N.; de Freitas, C.D.T.; Ramos, M.V. Latex proteins downregulate inflammation and restores blood-coagulation homeostasis in acute Salmonella infection. Mem. Inst. Oswaldo Cruz, 2020, 115, e200458.
[http://dx.doi.org/10.1590/0074-02760200458] [PMID: 33237133]
[41]
Nunes, M.O.; Fátima Goebel de Souza, T.; Pierdoná, T.M.; Ramos, M.V.; Ferreira, K.Q.; Duarte, R.S.; Shahwar, D.E.; Wilke, D.V.; Wong, D.V.T.; Alencar, N.M.N. In vitro biocompatibility and wound healing properties of latex proteins dressing. Toxicol. In Vitro, 2021, 76, 105230.
[http://dx.doi.org/10.1016/j.tiv.2021.105230] [PMID: 34343654]

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