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Metformin improves the therapeutic efficacy of low-dose albendazole against experimental alveolar echinococcosis

Published online by Cambridge University Press:  20 October 2021

Julia A. Loos ,
Magalí Coccimiglio ,
María Celeste Nicolao ,
Christian Rodriguez Rodrigues  and
Andrea C. Cumino Open the ORCID record for Andrea C. Cumino [Opens in a new window]
Julia A. Loos
Affiliation:
Laboratorio de Zoonosis Parasitarias, IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes 3350, Nivel Cero, (7600) Mar del Plata, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Magalí Coccimiglio
Affiliation:
Laboratorio de Zoonosis Parasitarias, IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes 3350, Nivel Cero, (7600) Mar del Plata, Argentina
María Celeste Nicolao
Affiliation:
Laboratorio de Zoonosis Parasitarias, IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes 3350, Nivel Cero, (7600) Mar del Plata, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Christian Rodriguez Rodrigues
Affiliation:
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes 3350, Nivel 2, (7600) Mar del Plata, Argentina
Andrea C. Cumino*
Affiliation:
Laboratorio de Zoonosis Parasitarias, IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes 3350, Nivel Cero, (7600) Mar del Plata, Argentina Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes 3350, Nivel 2, (7600) Mar del Plata, Argentina
*
Author for correspondence: Andrea C. Cumino, E-mail: acumino@gmail.com
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Abstract

Alveolar echinococcosis (AE) is a severe disease caused by Echinococcus multilocularis. Its chemotherapeutic treatment is based on benzimidazoles, which are rarely curative and cause several adverse effects. Therefore, it is necessary to develop alternative and safer chemotherapeutic strategies against AE. It has previously been shown that metformin (Met) exhibits considerable in vivo activity on an early-infection model of AE when administered at 50 mg kg−1 day−1 for 8 weeks. Here, the challenge is heightened by a 2-fold increase in parasite inoculum or by starting the treatment 6 weeks post-infection. In both cases, only the combination of Met (100 mg kg−1 day−1) together with a sub-optimal dose of albendazole (ABZ) (5 mg kg−1 day−1) led to a significant reduction in parasite weight compared to the untreated group. Coincidentally, drug combination showed the highest level of damage in E. multilocularis metacestodes. Likewise, Met alone or combined with ABZ led to a decrease in parasite glucose availability, which was evidenced as a lower intracystic glucose concentration. Therefore, the results demonstrate that combination therapy with Met and ABZ offers an alternative to improve the efficacy and reduce the toxicity of the high-dose ABZ monotherapy currently employed.

Keywords

Albendazolealveolar echinococcosisin vivo combination treatmentmetformin
Type
Research Article
Information
Parasitology , Volume 149 , Issue 1 , January 2022 , pp. 138 - 144
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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References

Ammann, RW and Eckert, J (1996) Cestodes: echinococcus. Gastroenterology Clinics 25, 655–689.CrossRefGoogle ScholarPubMed
Bouwknegt, M, Devleesschauwer, B, Graham, H, Robertson, L and van der Giessen, JW (2018) Prioritisation of food-borne parasites in Europe, 2016. Eurosurveillance 23, 17-00161.CrossRefGoogle ScholarPubMed
Bridges, HR, Jones, AJ, Pollak, MN and Hirst, J (2014) Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochemical Journal 462, 475–487.CrossRefGoogle ScholarPubMed
Brunetti, E, Kern, P and Vuitton, DA and Writing Panel for the WHO-IWGE (2010) Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Tropica 114, 1–16.CrossRefGoogle ScholarPubMed
Chaiteerakij, R, Petersen, GM, Bamlet, WR, Chaffee, KG, Zhen, DB, Burch, PA, Leof, ER, Roberts, LR and Oberg, AL (2016) Metformin use and survival of patients with pancreatic cancer: a cautionary lesson. Journal of Clinical Oncology 34, 1898.CrossRefGoogle ScholarPubMed
Cumino, AC, Elissondo, MC and Denegri, GM (2009) Flubendazole interferes with a wide spectrum of cell homeostatic mechanisms in Echinococcus granulosus protoscoleces. Parasitology International 58, 270–277.CrossRefGoogle ScholarPubMed
Deplazes, P, Rinaldi, L, Alvarez, R, Torgerson, CA, Harandi, PR, Romig, TMF, Antolova, D, Schurer, JM, Lahmar, S, Cringoli, G, Magambo, J, Thompson, RCA and Jenkins, EJ (2017) Global distribution of alveolar and cystic echinococcosis. Advances in Parasitology 95, 315–493.CrossRefGoogle ScholarPubMed
Enkai, S, Kouguchi, H, Inaoka, DK, Irie, T, Yagi, K and Kita, K (2021) In vivo efficacy of combination therapy with albendazole and atovaquone against primary hydatid cysts in mice. European Journal of Clinical Microbiology & Infectious Diseases 40, 1815–1820.CrossRefGoogle ScholarPubMed
Foucquier, J and Guedj, M (2015) Analysis of drug combinations: current methodological landscape. Pharmacology Research & Perspectives 3, e00149.CrossRefGoogle ScholarPubMed
Hemphill, A and Gottstein, B (1995) Immunology and morphology studies on the proliferation of in vitro cultivated Echinococcus multilocularis metacestodes. Parasitology Research 81, 605–614.CrossRefGoogle ScholarPubMed
Hemphill, A, Stadelmann, B, Rufener, R, Spiliotis, M, Boubaker, G, Müller, J, Müller, N, Gorgas, D and Gottstein, B (2014) Treatment of echinococcosis: albendazole and mebendazole–what else? Parasite 21, 70.CrossRefGoogle ScholarPubMed
Kern, P, Menezes da Silva, A, Akhan, O, Müllhaupt, B, Vizcaychipi, KA, Budke, C and Vuitton, DA (2017) The echinococcoses: diagnosis, clinical management and burden of disease. Advances in Parasitology 96, 259–369.CrossRefGoogle ScholarPubMed
Kobylinski, KC, Alout, H, Foy, BD, Clements, A, Adisakwattana, P, Swierczewski, BE and Richardson, JH (2014) Rationale for the coadministration of albendazole and ivermectin to humans for malaria parasite transmission control. The American Journal of Tropical Medicine and Hygiene 91, 655–662.CrossRefGoogle ScholarPubMed
Koziol, U, Rauschendorfer, T, Rodríguez, LZ, Krohne, G and Brehm, K (2014) The unique stem cell system of the immortal larva of the human parasite Echinococcus multilocularis. Evodevo 5, 1–23.10.1186/2041-9139-5-10CrossRefGoogle ScholarPubMed
Lacey, E (1990) Mode of action of benzimidazoles. Parasitology Today 6, 112–115.CrossRefGoogle ScholarPubMed
Lima, FR, Ferreira, LDM, Malta, TA, Bonyek-Silva, I, Santos, RL, Tavares, NM, de Carvalho Filho, EM and Arruda, S (2020) Metformin promotes susceptibility to experimental Leishmania braziliensis infection. Memórias do Instituto Oswaldo Cruz 115, e200272.CrossRefGoogle ScholarPubMed
Loos, JA and Cumino, AC (2015) In vitro anti-echinococcal and metabolic effects of metformin involve activation of AMP-activated protein kinase in larval stages of Echinococcus granulosus. PLoS ONE 10, e0126009.CrossRefGoogle ScholarPubMed
Loos, JA, Caparros, PA, Nicolao, MC, Denegri, GM and Cumino, AC (2014) Identification and pharmacological induction of autophagy in the larval stages of Echinococcus granulosus: an active catabolic process in calcareous corpuscles. International Journal for Parasitology 44, 415–427.CrossRefGoogle ScholarPubMed
Loos, JA, Dávila, VA, Rodrígues, CR, Petrigh, R, Zoppi, JA, Crocenzi, FA and Cumino, AC (2017) Metformin exhibits preventive and therapeutic efficacy against experimental cystic echinococcosis. PLoS Neglected Tropical Diseases 11, e0005370.CrossRefGoogle ScholarPubMed
Loos, JA, Dávila, VA, Brehm, K and Cumino, AC (2020) Metformin suppresses development of the Echinococcus multilocularis larval stage by targeting the TOR pathway. Antimicrobial Agents and Chemotherapy 64, e01808-19.CrossRefGoogle ScholarPubMed
Lundström-Stadelmann, B, Rufener, R, Ritler, D, Zurbriggen, R and Hemphill, A (2019) The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis. Food and Waterborne Parasitology 15, e00040.CrossRefGoogle ScholarPubMed
Lv, Z and Guo, Y (2020) Metformin and its benefits for various diseases. Frontiers in Endocrinology 11, 191. https://doi.org/10.3389/fendo.2020.00191.CrossRefGoogle ScholarPubMed
Martínez-Flórez, A, Galizzi, M, Izquierdo, L, Bustamante, JM, Rodriguez, A and Rodriguez, F (2020) Repurposing bioenergetic modulators against protozoan parasites responsible for tropical diseases. International Journal of Parasitology: Drugs and Drug Resistance 14, 17–27.Google ScholarPubMed
Matsumoto, J, Sakamoto, K, Shinjyo, N, Kido, Y, Yamamoto, N, Yagi, K, Miyoshi, H, Nonaka, N, Katakura, K, Kita, K and Oku, Y (2008) Anaerobic NADH-fumarate reductase system is predominant in the respiratory chain of Echinococcus multilocularis, providing a novel target for the chemotherapy of alveolar echinococcosis. Antimicrobial Agents and Chemotherapy 52, 164–170.CrossRefGoogle ScholarPubMed
McManus, DP and Smyth, JD (1982) Intermediary carbohydrate metabolism in protoscoleces of Echinococcus granulosus (horse and sheep strains) and E. multilocularis. Parasitology 84, 351–366.CrossRefGoogle ScholarPubMed
Morales, DR and Morris, AD (2015) Metformin in cancer treatment and prevention. Annual Review of Medicine 66, 17–29.CrossRefGoogle ScholarPubMed
Othman, AA, Abou Rayia, DM, Ashour, DS, Saied, EM, Zineldeen, DH and El-Ebiary, AA (2016) Atorvastatin and metformin administration modulates experimental Trichinella spiralis infection. Parasitology International 65, 105–112.CrossRefGoogle ScholarPubMed
Quinn, BJ, Kitagawa, H, Memmott, RM, Gills, JJ and Dennis, PA (2013) Repositioning metformin for cancer prevention and treatment. Trends in Endocrinology & Metabolism 24, 469–480.CrossRefGoogle ScholarPubMed
Ritler, D, Rufener, R, Li, JV, Kämpfer, U, Müller, J, Bühr, C, Schürch, S and Lundström-Stadelmann, B (2019) In vitro metabolomic footprint of the Echinococcus multilocularis metacestode. Scientific Reports 9, 1–13.CrossRefGoogle ScholarPubMed
Romig, T, Deplazes, P, Jenkins, D, Giraudoux, P, Massolo, A, Craig, PS, Wassermann, M, Takahashi, K and de la Rue, M (2017) Ecology and life cycle patterns of Echinococcus species. Advances in Parasitology 95, 213–314.CrossRefGoogle ScholarPubMed
Rufener, R, Dick, L, D'Ascoli, L, Ritler, D, Hizem, A, Wells, TN, Hemphill, A and Lundström-Stadelmann, B (2018) Repurposing of an old drug: in vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis. International Journal of Parasitology: Drugs and Drug Resistance 8, 440–450.Google ScholarPubMed
Short, S, Fielder, E, Miwa, S and von Zglinicki, T (2019) Senolytics and senostatics as adjuvant tumour therapy. EBioMedicine 41, 683–692.CrossRefGoogle ScholarPubMed
Siles-Lucas, M and Hemphill, A (2002) Cestode parasites: application of in vivo and in vitro models for studies on the host-parasite relationship. Advances in Parasitology 51, 133–230.CrossRefGoogle ScholarPubMed
Spicher, M, Roethlisberger, C, Lany, C, Stadelmann, B, Keiser, J, Ortega-Mora, LM, Gottstein, B and Hemphill, A (2008) In vitro and in vivo treatments of echinococcus protoscoleces and metacestodes with artemisinin and artemisinin derivatives. Antimicrobial Agents and Chemotherapy 52, 3447–3450.CrossRefGoogle ScholarPubMed
Spiliotis, M and Brehm, K (2009) Axenic in vitro cultivation of Echinococcus multilocularis metacestode vesicles and the generation of primary cell cultures. Host-Pathogen Interactions 470, 245–262.CrossRefGoogle ScholarPubMed
Vera, IM, Ruivo, MTG, Rocha, LFL, Marques, S, Bhatia, SN, Mota, MM and Mancio-Silva, L (2019) Targeting liver stage malaria with metformin. JCI Insight 4, e127441.CrossRefGoogle ScholarPubMed
Vial, G, Detaille, D and Guigas, B (2019) Role of mitochondria in the mechanism (s) of action of metformin. Frontiers in Endocrinology 10, 294.CrossRefGoogle ScholarPubMed
Wheaton, WW, Weinberg, SE, Hamanaka, RB, Soberanes, S, Sullivan, LB, Anso, E, Glasauer, A, Dufour, E, Mutlu, GM, Budigner, GS and Chandel, NS (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. elife 3, e02242.CrossRefGoogle ScholarPubMed
WHO Informal Working Group (1996) Guidelines for treatment of cystic and alveolar echinococcosis in humans K. Bulletin of the WHO 74, 231–242.Google Scholar
Wu, D, Hu, D, Chen, H, Shi, G, Fetahu, IS, Wu, F, Rabidou, K, Fang, R, Tan, L, Xu, S, Liu, H, Argueta, C, Zhang, L, Mao, F, Yan, G, Chen, J, Dong, Z, Lv, R, Xu, Y, Wang, M, Ye, Y, Zhang, S, Duquette, D, Geng, S, Yin, C, Lian, CG, Murphy, GF, Adler, GK, Garg, R, Lynch, L, Yang, P, Li, Y, Lan, F, Fan, J, Shi, Y and Shi, YG (2018) Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 559, 637–641.CrossRefGoogle ScholarPubMed
Yi, G, He, Z, Zhou, X, Xian, L, Yuan, T, Jia, X, Hong, J, He, L and Liu, J (2013) Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. International Journal of Oncology 43, 1503–1510.CrossRefGoogle ScholarPubMed
Zeuzem, S, Jacobson, IM, Baykal, T, Marinho, RT, Poordad, F, Bourlière, M, Sulkowski, MS, Wedemeyer, H, Tam, E, Desmond, P, Jensen, DM, Di Bisceglie, AM, Varunok, P, Hassanein, T, Xiong, J, Pilot-Matias, T, DaSilva-Tillmann, B, Larsen, L, Podsadecki, T and Bernstein, B (2014) Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. New England Journal of Medicine 370, 1604–1614.CrossRefGoogle ScholarPubMed
Zhang, Z, Zhou, L, Xie, N, Nice, EC, Zhang, T, Cui, Y and Huang, C (2020) Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduction and Targeted Therapy 5, 1–25.CrossRefGoogle ScholarPubMed
Zhuang, Y, Chan, DK, Haugrud, AB and Miskimins, WK (2014) Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo. PLoS ONE 9, e108444.CrossRefGoogle ScholarPubMed
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