Abstract
Chemotherapy is the most common treatment for breast cancer and its metastasis; however, it affects the patients’ quality of life. Previously, it was demonstrated that milk fermented by Lactobacillus casei CRL431 (probiotic fermented milk (PFM)) exerted benefits against breast cancer metastasis by modulating the immune response in a mouse model. The aim of this work was to evaluate PFM administration on the side effects of capecitabine and on its anti-tumour/anti-metastatic effects. In vitro, 4T1 breast cancer cells were treated with capecitabine in the presence of immune cells’ conditioned media from mice administered with PFM. Cell viability was evaluated by MTT assay. In vivo, BALB/c mice (healthy, bearing breast cancer or with potential metastasis) were treated or not with capecitabine and administered with PFM. Blood cell counts, intestinal damages, lung histology and serum cytokines were evaluated. Results showed that capecitabine’s toxicity on 4T1 cells was improved by the immune cells from mice that received PFM when the lower dose of capecitabine was evaluated. PFM reduced capecitabine side effects in all the mouse models and decreased intestinal mucositis and mortality. PFM administration to mice under chemotherapy maintained the anti-cancer/anti-metastasis effect of capecitabine with similar or decreased values for serum IL-10 and TNF-α and decreased IL-6, a cytokine related to poor prognosis in advanced cancer patients. In addition, PFM by itself reduced metastasis without side effects and improved the host’s immune response. PFM has a potential to be administered as an immune adjuvant in patients under chemotherapy without affecting the treatment.
Key points
• Milk fermented by L. casei CRL431 (PFM) diminished capecitabine side effects.
• Capecitabine’s toxicity on 4T1 cells was improved by the PFM-stimulated immune cells.
• PFM maintained anti-cancer/anti-metastasis effect of capecitabine in mouse models.
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References
Abd El-Atti S, Wasicek K, Mark S, Hegazi R (2009) Use of probiotics in the management of chemotherapy-induced diarrhea: a case study. JPEN J Parenter Enteral Nutr 33(5):569–570. https://doi.org/10.1177/0148607109332004
American-Cancer-Society (2017) Breast cancer facts & figures 2017-2018. Atlanta: American Cancer Society, Inc. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed 11 Nov 2020
An J, Ha EM (2016) Combination therapy of Lactobacillus plantarum supernatant and 5-fluouracil increases chemosensitivity in colorectal cancer cells. J Microbiol Biotechnol 26(8):1490–1503. https://doi.org/10.4014/jmb.1605.05024
Aragon F, Carino S, Perdigon G, de Moreno de LeBlanc A (2014) The administration of milk fermented by the probiotic Lactobacillus casei CRL 431 exerts an immunomodulatory effect against a breast tumour in a mouse model. Immunobiology 219(6):457–464 S0171-2985(14)00029–1
Aragon F, Carino S, Perdigon G, de Moreno de LeBlanc A (2015) Inhibition of growth and metastasis of breast cancer in mice by milk fermented with Lactobacillus casei CRL 431. J Immunother 38(5):185–196. https://doi.org/10.1097/CJI.0000000000000079
Chen C, Chan HM, Kubow S (2007) Kefir extracts suppress in vitro proliferation of estrogen-dependent human breast cancer cells but not normal mammary epithelial cells. J Med Food 10(3):416–422. https://doi.org/10.1089/jmf.2006.236
Devaraj NK, Suppiah S, Veettil SK, Ching SM, Lee KW, Menon RK, Soo MJ, Deuraseh I, Hoo FK, Sivaratnam D (2019) The effects of probiotic supplementation on the incidence of diarrhea in cancer patients receiving radiation therapy: a systematic review with meta-analysis and trial sequential analysis of randomized controlled trials. Nutrients 11(12). https://doi.org/10.3390/nu11122886
Dillekås H, Rogers MS, Straume O (2019) Are 90% of deaths from cancer caused by metastases? Cancer Med 8(12):5574–5576. https://doi.org/10.1002/cam4.2474
FAO/WHO (2002) Probiotics in food Health and nutritional properties and guidelines for evaluation. Food and Agriculture Organization of the United Nations and World Health Organization Expert Consultation Report .Available from http://www.fao.org/3/a-a0512e.pdf. Accessed 11 Nov 2020
Gong X, Moghaddam MJ, Sagnella SM, Conn CE, Danon SJ, Waddington LJ, Drummond CJ (2011) Lamellar crystalline self-assembly behaviour and solid lipid nanoparticles of a palmityl prodrug analogue of capecitabine--a chemotherapy agent. Colloids Surf B Biointerfaces 85(2):349–359. https://doi.org/10.1016/j.colsurfb.2011.03.007
Hassan Z, Mustafa S, Rahim RA, Isa NM (2016) Anti-breast cancer effects of live, heat-killed and cytoplasmic fractions of Enterococcus faecalis and Staphylococcus hominis isolated from human breast milk. In Vitro Cell Dev Biol Anim 52(3):337–348. https://doi.org/10.1007/s11626-015-9978-8
Hu M, Wu X, Luo M, Wei H, Xu D, Xu F (2020) Lactobacillus rhamnosus FLRH93 protects against intestinal damage in mice induced by 5-fluorouracil. J Dairy Sci 103(6):5003–5018. https://doi.org/10.3168/jds.2019-17836
Kassayova M, Bobrov N, Strojny L, Orendas P, Demeckova V, Jendzelovsky R, Kubatka P, Kiskova T, Kruzliak P, Adamkov M, Bomba A, Fedorocko P (2016) Anticancer and Immunomodulatory effects of Lactobacillus plantarum LS/07, inulin and melatonin in NMU-induced rat model of breast cancer. Anticancer Res 36(6):2719–2728
Ke YY, Tsai CH, Yu HM, Jao YC, Fang JM, Wong CH (2015) Latifolicinin a from a fermented soymilk product and the structure-activity relationship of synthetic analogues as inhibitors of breast cancer cell growth. J Agric Food Chem 63(44):9715–9721. https://doi.org/10.1021/acs.jafc.5b04028
Levit R, Savoy de Giori G, de Moreno de LeBlanc A, LeBlanc JG (2018) Effect of riboflavin-producing bacteria against chemically induced colitis in mice. J Appl Microbiol 124(1):232–240. https://doi.org/10.1111/jam.13622
Lippitz BE (2013) Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol 14(6):e218–e228. https://doi.org/10.1016/s1470-2045(12)70582-x
Lippitz BE, Harris RA (2016) Cytokine patterns in cancer patients: a review of the correlation between interleukin 6 and prognosis. Oncoimmunology 5(5):e1093722. https://doi.org/10.1080/2162402x.2015.1093722
Mego M, Holec V, Drgona L, Hainova K, Ciernikova S, Zajac V (2013) Probiotic bacteria in cancer patients undergoing chemotherapy and radiation therapy. Complement Ther Med 21(6):712–723. https://doi.org/10.1016/j.ctim.2013.08.018
Mendez Utz VE, Perdign G, de Moreno de LeBlanc A (2019a) Oral administration of milk fermented by Lactobacillus casei CRL431 was able to decrease metastasis from breast cancer in a murine model by modulating immune response locally in the lungs. J Funct Foods 54:263–270. https://doi.org/10.1016/j.jff.2019.01.026
Mendez Utz VE, Perdigón G, de Moreno de LeBlanc A (2019b) Milk fermented by Lactobacillus casei CRL431 modifies cytokine profiles associated to different stages of breast cancer development in mice. Benefic Microbes 10(6):689–697. https://doi.org/10.3920/bm2019.0011
Mendoza L (2019) Potential effect of probiotics in the treatment of breast cancer. Oncol Rev 13(2):422. https://doi.org/10.4081/oncol.2019.422
Miller AC, Elamin EM (2009) Use of probiotics for treatment of chemotherapy-induced diarrhea: is it a myth? JPEN J Parenter Enteral Nutr 33(5):573–574. https://doi.org/10.1177/0148607109336596
Motevaseli E, Khorramizadeh MR, Hadjati J, Bonab SF, Eslami S, Ghafouri-Fard S (2018) Investigation of antitumor effects of Lactobacillus crispatus in experimental model of breast cancer in BALB/c mice. Immunotherapy 10(2):119–129. https://doi.org/10.2217/imt-2017-0088
Nami Y, Abdullah N, Haghshenas B, Radiah D, Rosli R, Khosroushahi AY (2014) Assessment of probiotic potential and anticancer activity of newly isolated vaginal bacterium Lactobacillus plantarum 5BL. Microbiol Immunol 58(9):492–502. https://doi.org/10.1111/1348-0421.12175
Oliveira Silva E, Cruz de Carvalho T, Parshikov IA, Alves dos Santos R, Silva Emery F, Jacometti Cardoso Furtado NA (2014) Cytotoxicity of lapachol metabolites produced by probiotics. Lett Appl Microbiol 59(1):108–114. https://doi.org/10.1111/lam.12251
Osterlund P, Ruotsalainen T, Korpela R, Saxelin M, Ollus A, Valta P, Kouri M, Elomaa I, Joensuu H (2007) Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer 97(8):1028–1034. https://doi.org/10.1038/sj.bjc.6603990
Ranjbar S, Seyednejad SA, Azimi H, Rezaeizadeh H, Rahimi R (2019) Emerging roles of probiotics in prevention and treatment of breast cancer: a comprehensive review of their therapeutic potential. Nutr Cancer 71(1):1–12. https://doi.org/10.1080/01635581.2018.1557221
Sheikhpour E, Noorbakhsh P, Foroughi E, Farahnak S, Nasiri R, Neamatzadeh H (2018) A survey on the role of Interleukin-10 in breast cancer: a narrative. Rep Biochem Mol Biol 7(1):30–37
Shu Z, Li P, Yu B, Huang S, Chen Y (2020) The effectiveness of probiotics in prevention and treatment of cancer therapy-induced oral mucositis: a systematic review and meta-analysis. Oral Oncol 102:104559. https://doi.org/10.1016/j.oraloncology.2019.104559
Timmers L, Swart EL, Boons CC, Mangnus D, van de Ven PM, Peters GJ, Boven E, Hugtenburg JG (2012) The use of capecitabine in daily practice: a study on adherence and patients’ experiences. Patient Prefer Adherence 6:741–748. https://doi.org/10.2147/PPA.S36757
Tooley KL, Howarth GS, Lymn KA, Lawrence A, Butler RN (2011) Oral ingestion of Streptococcus thermophilus does not affect mucositis severity or tumor progression in the tumor-bearing rat. Cancer Biol Ther 12(2):131–138. https://doi.org/10.4161/cbt.12.2.15720
Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL (2004) Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 90(6):1190–1197. https://doi.org/10.1038/sj.bjc.6601676
Vyas D, Laput G, Vyas AK (2014) Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco Targets Ther 7:1015–1023. https://doi.org/10.2147/ott.s60114
Wei D, Heus P, van de Wetering FT, van Tienhoven G, Verleye L, Scholten RJ (2018) Probiotics for the prevention or treatment of chemotherapy- or radiotherapy-related diarrhoea in people with cancer. Cochrane Database Syst Rev 8:CD008831. https://doi.org/10.1002/14651858.CD008831.pub3
Zamberi NR, Abu N, Mohamed NE, Nordin N, Keong YS, Beh BK, Zakaria ZA, Nik Abdul Rahman NM, Alitheen NB (2016) The antimetastatic and antiangiogenesis effects of kefir water on murine breast cancer cells. Integr Cancer Ther 15(4):NP53–NP66. https://doi.org/10.1177/1534735416642862
Zhang Q, Kang X, Yang B, Wang J, Yang F (2008) Antiangiogenic effect of capecitabine combined with ginsenoside Rg3 on breast cancer in mice. Cancer Biother Radiopharm 23(5):647–653. https://doi.org/10.1089/cbr.2008.0532
Funding
This work was financially supported by CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas, project PIP 0697) and ANPCyT (Agencia Nacional de Promoción Científica y Tecnológica, projects 0301and 2554).
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V.E.M.U. and A.d.M.d.L. planned the research. V.E.M.U., D.P.V. and A.d.M.d.L. conducted the experimental research. V.E.M.U., G.P. and A.d.M.d.L. analysed the data. V.E.M.U and A.d.M.d.L. wrote the manuscript. G.P. made critical revisions of the manuscript. V.E.M.U., G.P. and A.d.M.d.L. approved the final version of the manuscript.
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Animal experiments were approved by the Animal Protection Committee of CERELA and all experiments comply with the current laws of Argentina and international organisations for the use of experimental animals.
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Méndez Utz, V.E., Pérez Visñuk, D., Perdigón, G. et al. Milk fermented by Lactobacillus casei CRL431 administered as an immune adjuvant in models of breast cancer and metastasis under chemotherapy. Appl Microbiol Biotechnol 105, 327–340 (2021). https://doi.org/10.1007/s00253-020-11007-x
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DOI: https://doi.org/10.1007/s00253-020-11007-x