Login Register Cart 0
Generic placeholder image

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Recombinant Human Lactoferrin Augments Epirubicin Chemotherapy in Solid Ehrlich Carcinoma Bearing Mice

Author(s): Nahla E. El-Ashmawy, Eman G. Khedr, Amira Y. El-Kady and Ghada M. Al-Ashmawy*

Volume 18, Issue 3, 2023

Published on: 24 June, 2022

Page: [345 - 354] Pages: 10

DOI: 10.2174/1574886317666220429102445

Price: $65

Abstract

Background: Lactoferrin (LF) is a member of the transferrin family, which is known for its immunomodulatory properties. LF has been widely used as an anticancer medication in various cancers including breast cancer.

Aims: The current study aimed to examine the molecular mechanisms underlying the therapeutic potential of recombinant human lactoferrin (rhLF), either alone or combined with epirubicin (EPI), in mice bearing solid Ehrlich carcinoma (SEC).

Methods: SEC-bearing female mice (n=40) were divided into 4 equal groups. Mice were given rhLF orally (100mg/kg/mouse) daily and/or EPI i.p (8mg/kg/mouse). The experiment lasted 14 days, after which samples were collected to measure IL-18 and phosphorylated c-Jun N-terminal kinase (p-JNK) by ELISA and p53 gene expression by real-time PCR.

Results: Administration of rhLF, either alone or combined with EPI, markedly decreased the tumor volume and increased tumor inhibition rate as well as survival rate compared to either tumor control group or EPI-mono treated group. In addition, co-administration of rhLF and EPI increased the level of activated JNKs and expression of p53 in tumor tissues compared to the tumor, control group, exhibiting their pro-apoptotic properties. Moreover, the combined treatment with rhLF and EPI elevated IL-18 level in the intestinal mucosa compared to other experimental groups with a possible immune-enhancing effect.

Conclusion: Recombinant human lactoferrin exhibited potential anticancer and immune-enhancing properties in mice with breast cancer. Co-treatment with rhLF and EPI proved to be a promising strategy in cancer treatment.

Keywords: Lactoferrin, epirubicin, phosphorylated c-Jun N-terminal kinase, breast cancer, solid ehrlich carcinoma, p53.

« Previous Next »
[1]
Azamjah, N.; Soltan-Zadeh, Y.; Zayeri, F. Global trend of breast cancer mortality rate: A 25-year study. Asian Pac. J. Cancer Prev., 2019, 20(7), 2015-2020.
[http://dx.doi.org/10.31557/APJCP.2019.20.7.2015] [PMID: 31350959]
[2]
Zhang, Y.; Lima, C.F.; Rodrigues, L.R. Anticancer effects of lactoferrin: Underlying mechanisms and future trends in cancer therapy. Nutr. Rev., 2014, 72(12), 763-773.
[http://dx.doi.org/10.1111/nure.12155] [PMID: 25406879]
[3]
Chang, R.; Ng, T.B.; Sun, W.Z. Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int. J. Antimicrob. Agents, 2020, 56(3), 106118.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.106118] [PMID: 32738305]
[4]
Pereira, C.S.; Guedes, J.P.; Gonçalves, M.; Loureiro, L.; Castro, L. Gerós, H.; Rodrigues, L.R.; Côrte-Real, M. Lactoferrin selectively triggers apoptosis in highly metastatic breast cancer cells through inhibition of plasmalemmal V-H+-ATPase. Oncotarget, 2016, 7(38), 62144-62158.
[http://dx.doi.org/10.18632/oncotarget.11394] [PMID: 27556694]
[5]
Launchbury, A.P.; Habboubi, N. Epirubicin and doxorubicin: A comparison of their characteristics, therapeutic activity and toxicity. Cancer Treat. Rev., 1993, 19(3), 197-228.
[http://dx.doi.org/10.1016/0305-7372(93)90036-Q] [PMID: 8334677]
[6]
Chen, H.; Qin, Y.; Zhang, Q.; Jiang, W.; Tang, L.; Liu, J.; He, Q. Lactoferrin modified doxorubicin-loaded procationic liposomes for the treatment of gliomas. Eur. J. Pharm. Sci., 2011, 44(1-2), 164-173.
[http://dx.doi.org/10.1016/j.ejps.2011.07.007] [PMID: 21782939]
[7]
Shankaranarayanan, J.S.; Kanwar, J.R.; Al-Juhaishi, A.J.A.; Kanwar, R.K. Author correction: Doxorubicin conjugated to immunomodulatory anticancer lactoferrin displays improved cytotoxicity overcoming prostate cancer chemo resistance and inhibits tumour development in TRAMP mice. Sci. Rep., 2019, 9(1), 6529.
[http://dx.doi.org/10.1038/s41598-019-42459-5] [PMID: 31024014]
[8]
Sakai, M.; Ferraz-de-Paula, V.; Pinheiro, M.L.; Ribeiro, A.; Quinteiro-Filho, W.M.; Rone, M.B.; Martinez-Arguelles, D.B.; Dagli, M.L.; Papadopoulos, V.; Palermo-Neto, J. Translocator protein (18 kDa) mediates the pro-growth effects of diazepam on Ehrlich tumor cells in vivo. Eur. J. Pharmacol., 2010, 626(2-3), 131-138.
[http://dx.doi.org/10.1016/j.ejphar.2009.09.036] [PMID: 19782064]
[9]
Elbialy, N.; Abdelhamid, M.; Youssef, T. Low power argon laser-induced thermal therapy for subcutaneous Ehrlich carcinoma in mice using spherical gold nanoparticles. J. Biomed. Nanotechnol., 2010, 6(6), 687-693.
[http://dx.doi.org/10.1166/jbn.2010.1166] [PMID: 21361134]
[10]
Bassiony, H.; Sabet, S.; Salah El-Din, T.A.; Mohamed, M.M.; El-Ghor, A.A. Magnetite nanoparticles inhibit tumor growth and upregulate the expression of p53/p16 in Ehrlich solid carcinoma bearing mice. PLoS One, 2014, 9(11), e111960.
[http://dx.doi.org/10.1371/journal.pone.0111960] [PMID: 25375144]
[11]
Yang, F.; Lei, Q.; Li, L.; He, J.C.; Zeng, J.; Luo, C.; Yeung, S.J.; Yang, R. Delivery of epirubicin via slow infusion as a strategy to mitigate chemotherapy-induced cardiotoxicity. PLoS One, 2017, 12(11), e0188025.
[http://dx.doi.org/10.1371/journal.pone.0188025] [PMID: 29131861]
[12]
Ibrahim, H.M.; Mohamed, A.H.; Salem, M.L.; Osman, G.Y.; Morsi, D.S. Anti-neoplastic and immunomodulatory potency of co-treatment based on bovine lactoferrin and/or muramyl dipeptide in tumor-bearing mice. Toxicol. Res. (Camb.), 2020, 9(2), 137-147.
[http://dx.doi.org/10.1093/toxres/tfaa012] [PMID: 32440345]
[13]
El-Ashmawy, N.E.; Khedr, N.F.; El-Bahrawy, H.A.; Abo Mansour, H.E. Ginger extract adjuvant to doxorubicin in mammary carcinoma: Study of some molecular mechanisms. Eur. J. Nutr., 2018, 57(3), 981-989.
[http://dx.doi.org/10.1007/s00394-017-1382-6] [PMID: 28229277]
[14]
Wang, Z.; Zhao, X.; Liu, Y.; Wang, T.; Li, K. New therapeutic strategies based on interference with telomeric DNA synthesis of tumor cells to suppress the growth of tumors. RSC Advances, 2018, 8, 25001-25007.
[http://dx.doi.org/10.1039/C8RA02599A]
[15]
El-Ashmawy, N.E.; Khedr, E.G.; Ebeid, E.M.; Salem, M.L.; Zidan, A.A.; Mosalam, E.M. Enhanced anticancer effect and reduced toxicity of doxorubicin in combination with thymoquinone released from poly-N-acetyl glucosamine nanomatrix in mice bearing solid Ehrlish carcinoma. Eur. J. Pharm. Sci., 2017, 109, 525-532.
[http://dx.doi.org/10.1016/j.ejps.2017.09.012] [PMID: 28890201]
[16]
El-Ashmawy, N.E.; Al-Ashmawy, G.M.; Amr, E.A.; Khedr, E.G. Inhibition of lovastatin- and docosahexaenoic acid-initiated autophagy in triple negative breast cancer reverted resistance and enhanced cytotoxicity. Life Sci., 2020, 259, 118212.
[http://dx.doi.org/10.1016/j.lfs.2020.118212] [PMID: 32768581]
[17]
Field, A. Discovering statistics using SPSS, 3rd ed; Sage Publications: London, 2009.
[18]
Greaves, M.; Maley, C.C. Clonal evolution in cancer. Nature, 2012, 481(7381), 306-313.
[http://dx.doi.org/10.1038/nature10762] [PMID: 22258609]
[19]
Khedr, N.F.; Khalil, R.M. Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin. Tumour Biol., 2015, 36(12), 9267-9275.
[http://dx.doi.org/10.1007/s13277-015-3655-0] [PMID: 26099723]
[20]
Iglesias-Figueroa, B.F. Siqueiros-Cendón, T.S.; Gutierrez, D.A.; Aguilera, R.J.; Espinoza-Sánchez, E.A.; Arévalo-Gallegos, S.; Varela-Ramirez, A.; Rascón-Cruz, Q. Recombinant human lactoferrin induces apoptosis, disruption of F-actin structure and cell cycle arrest with selective cytotoxicity on human triple negative breast cancer cells. Apoptosis, 2019, 24(7-8), 562-577.
[http://dx.doi.org/10.1007/s10495-019-01539-7] [PMID: 30941553]
[21]
Yang, N. Strøm, M.B.; Mekonnen, S.M.; Svendsen, J.S.; Rekdal, O. The effects of shortening lactoferrin derived peptides against tumour cells, bacteria and normal human cells. J. Pept. Sci., 2004, 10(1), 37-46.
[http://dx.doi.org/10.1002/psc.470] [PMID: 14959890]
[22]
Yamada, Y.; Sato, R.; Kobayashi, S.; Hankanga, C.; Inanami, O.; Kuwabara, M.; Momota, Y.; Tomizawa, N.; Yasuda, J. The antiproliferative effect of bovine lactoferrin on canine mammary gland tumor cells. J. Vet. Med. Sci., 2008, 70(5), 443-448.
[http://dx.doi.org/10.1292/jvms.70.443] [PMID: 18525164]
[23]
Kanwar, J.R.; Palmano, K.P.; Sun, X.; Kanwar, R.K.; Gupta, R.; Haggarty, N.; Rowan, A.; Ram, S.; Krissansen, G.W. ‘Iron-saturated’ lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy. Immunol. Cell Biol., 2008, 86(3), 277-288.
[http://dx.doi.org/10.1038/sj.icb.7100163] [PMID: 18268518]
[24]
Massodi, I.; Thomas, E.; Raucher, D. Application of thermally responsive elastin-like polypeptide fused to a lactoferrin-derived peptide for treatment of pancreatic cancer. Molecules, 2009, 14(6), 1999-2015.
[http://dx.doi.org/10.3390/molecules14061999] [PMID: 19513001]
[25]
Kruzel, M.L.; Zimecki, M.; Actor, J.K. Lactoferrin in a Context of Inflammation-Induced Pathology. Front. Immunol., 2017, 8, 1438.
[http://dx.doi.org/10.3389/fimmu.2017.01438] [PMID: 29163511]
[26]
Arcella, A.; Oliva, M.A.; Staffieri, S.; Aalberti, S.; Grillea, G.; Madonna, M.; Bartolo, M.; Pavone, L.; Giangaspero, F.; Cantore, G.; Frati, A. In vitro and in vivo effect of human lactoferrin on glioblastoma growth. J. Neurosurg., 2015, 123(4), 1026-1035.
[http://dx.doi.org/10.3171/2014.12.JNS14512] [PMID: 26186026]
[27]
Wolf, J.S.; Li, G.; Varadhachary, A.; Petrak, K.; Schneyer, M.; Li, D.; Ongkasuwan, J.; Zhang, X.; Taylor, R.J.; Strome, S.E.; O’Malley, B.W. Jr Oral lactoferrin results in T cell-dependent tumor inhibition of head and neck squamous cell carcinoma in vivo. Clin. Cancer Res., 2007, 13(5), 1601-1610.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2008] [PMID: 17332307]
[28]
Sharma, A.; Shandilya, U.K.; Sodhi, M.; Mohanty, A.K.; Jain, P.; Mukesh, M. Evaluation of milk colostrum derived lactoferrin of Sahiwal (Bos indicus) and Karan Fries (Cross-Bred) cows for its anti-cancerous potential. Int. J. Mol. Sci., 2019, 20(24), 6318.
[http://dx.doi.org/10.3390/ijms20246318] [PMID: 31847364]
[29]
Oh, S.M.; Pyo, C.W.; Kim, Y.; Choi, S.Y. Neutrophil lactoferrin upregulates the human p53 gene through induction of NF-kappaB activation cascade. Oncogene, 2004, 23(50), 8282-8291.
[http://dx.doi.org/10.1038/sj.onc.1208021] [PMID: 15378004]
[30]
Luo, Y.; Fu, X.; Han, B.; Zhang, F.; Yuan, L.; Men, H.; Zhang, S.; Tian, S.; Dong, B.; Meng, M. The apoptosis mechanism of epirubicin combined with bcg on human bladder cancer cells. Anticancer. Agents Med. Chem., 2020, 20(13), 1571-1581.
[http://dx.doi.org/10.2174/1871520620666200502004002] [PMID: 32357825]
[31]
Chen, J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb. Perspect. Med., 2016, 6(3), a026104.
[http://dx.doi.org/10.1101/cshperspect.a026104] [PMID: 26931810]
[32]
Chea, C.; Miyauchi, M.; Inubushi, T.; Febriyanti Ayuningtyas, N.; Subarnbhesaj, A.; Nguyen, P.T.; Shrestha, M.; Haing, S.; Ohta, K.; Takata, T. Molecular mechanism of inhibitory effects of bovine lactoferrin on the growth of oral squamous cell carcinoma. PLoS One, 2018, 13(1), e0191683.
[http://dx.doi.org/10.1371/journal.pone.0191683] [PMID: 29381751]
[33]
Moreno-Expósito, L.; Illescas-Montes, R.; Melguizo-Rodríguez, L.; Ruiz, C.; Ramos-Torrecillas, J.; de Luna-Bertos, E. Multifunctional capacity and therapeutic potential of lactoferrin. Life Sci., 2018, 195, 61-64.
[http://dx.doi.org/10.1016/j.lfs.2018.01.002] [PMID: 29307524]
[34]
Iigo, M.; Shimamura, M.; Matsuda, E.; Fujita, K.; Nomoto, H.; Satoh, J.; Kojima, S.; Alexander, D.B.; Moore, M.A.; Tsuda, H. Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa: A possible explanation for inhibition of carcinogenesis and metastasis. Cytokine, 2004, 25(1), 36-44.
[http://dx.doi.org/10.1016/j.cyto.2003.09.009] [PMID: 14687584]
[35]
Kuhara, T.; Yamauchi, K.; Tamura, Y.; Okamura, H. Oral administration of lactoferrin increases NK cell activity in mice via increased production of IL-18 and type I IFN in the small intestine. J. Interferon Cytokine Res., 2006, 26(7), 489-499.
[http://dx.doi.org/10.1089/jir.2006.26.489] [PMID: 16800788]
[36]
Figueiredo, N.; Chora, A.; Raquel, H.; Pejanovic, N.; Pereira, P.; Hartleben, B.; Neves-Costa, A.; Moita, C.; Pedroso, D.; Pinto, A.; Marques, S.; Faridi, H.; Costa, P.; Gozzelino, R.; Zhao, J.L.; Soares, M.P.; Gama-Carvalho, M.; Martinez, J.; Zhang, Q. Döring, G.; Grompe, M.; Simas, J.P.; Huber, T.B.; Baltimore, D.; Gupta, V.; Green, D.R.; Ferreira, J.A.; Moita, L.F. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity, 2013, 39(5), 874-884.
[http://dx.doi.org/10.1016/j.immuni.2013.08.039] [PMID: 24184056]
[37]
Angsutararux, P.; Luanpitpong, S.; Issaragrisil, S. Chemotherapy-induced cardiotoxicity: Overview of the roles of oxidative stress. Oxid. Med. Cell. Longev., 2015, 2015, 795602.
[http://dx.doi.org/10.1155/2015/795602] [PMID: 26491536]
[38]
Cutone, A.; Rosa, L.; Ianiro, G.; Lepanto, M.S.; Bonaccorsi di Patti, M.C.; Valenti, P.; Musci, G. Lactoferrin’s anti-cancer properties: Safety, selectivity, and wide range of action. Biomolecules, 2020, 10(3), 456.
[http://dx.doi.org/10.3390/biom10030456] [PMID: 32183434]
[39]
Lee, S.H.; Park, S.W.; Pyo, C.W.; Yoo, N.K.; Kim, J.; Choi, S.Y. Requirement of the JNK-associated Bcl-2 pathway for human lactoferrin-induced apoptosis in the Jurkat leukemia T cell line. Biochimie, 2009, 91(1), 102-108.
[http://dx.doi.org/10.1016/j.biochi.2008.05.004] [PMID: 18534198]
[40]
Zhang, J.L.; Han, X.; Shan, Y.J.; Zhang, L.W.; Du, M.; Liu, M.; Yi, H.X.; Ma, Y. Effect of bovine lactoferrin and human lactoferrin on the proliferative activity of the osteoblast cell line MC3T3-E1 in vitro. J. Dairy Sci., 2018, 101(3), 1827-1833.
[http://dx.doi.org/10.3168/jds.2017-13161] [PMID: 29290425]

Rights & Permissions Print Cite
Article Metrics
4
© 2024 Bentham Science Publishers | Privacy Policy