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Recombinant human lactoferrin carrying humanized glycosylation exhibits antileukemia selective cytotoxicity, microfilament disruption, cell cycle arrest, and apoptosis activities

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Summary

Lactoferrin has gained extensive attention due to its ample biological properties. In this study, recombinant human lactoferrin carrying humanized glycosylation (rhLf-h-glycan) expressed in the yeast Pichia pastoris SuperMan5, which is genetically glycoengineered to efficiently produce functional humanized glycoproteins inclosing (Man)5(GlcNAc)2 Asn-linked glycans, was analyzed, inspecting its potential toxicity against cancer cells. The live-cell differential nuclear staining assay was used to quantify the rhLf-h-glycan cytotoxicity, which was examined in four human cell lines: acute lymphoblastic leukemia (ALL) CCRF-CEM, T-cell lymphoblastic lymphoma SUP-T1, cervical adenocarcinoma HeLa, and as control, non-cancerous Hs27 cells. The defined CC50 values of rhLf-h-glycan in CCRF-CEM, SUP-T1, HeLa, and Hs27 cells were 144.45 ± 4.44, 548.47 ± 64.41, 350 ± 14.82, and 3359.07 ± 164 µg/mL, respectively. The rhLf-h-glycan exhibited a favorable selective cytotoxicity index (SCI), preferentially killing cancer cells: 23.25 for CCRF-CEM, 9.59 for HeLa, and 6.12 for SUP-T1, as compared with Hs27 cells. Also, rhLf-h-glycan showed significant antiproliferative activity (P < 0.0001) at 24, 48, and 72 h of incubation on CCRF-CEM cells. Additionally, it was observed via fluorescent staining and confocal microscopy that rhLf-h-glycan elicited apoptosis-associated morphological changes, such as blebbing, nuclear fragmentation, chromatin condensation, and apoptotic bodies in ALL cells. Furthermore, rhLf-h-glycan-treated HeLa cells revealed shrinkage of the microfilament structures, generating a speckled/punctuated pattern and also caused PARP-1 cleavage, a hallmark of apoptosis. Moreover, in ALL cells, rhLf-h-glycan altered cell cycle progression inducing the G2/M phase arrest, and caused apoptotic DNA fragmentation. Overall, our findings revealed that rhLf-h-glycan has potential as an anticancer agent and therefore deserves further in vivo evaluation.

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Acknowledgements

The authors thank the staff of the Border Biomedical Research Center at the University of Texas at El Paso (UTEP), in particular to Ms. Gladys Almodovar for cell culture expertise and the Cellular Characterization and Biorepository (CCB) Core Facility-UTEP.

Funding

The work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT), Mexico, to SN-B and by an internal grant (2016–2017) from the Facultad de Ciencias Químicas, at the Universidad Autónoma de Chihuahua, Mexico, to QR-C. Also, support grant from the Lizanell and Colbert Coldwell Foundation to ER-E and by the National Institute of General Medical Sciences-Support of Competitive Research (SCORE) grant 1SC3GM103713 to RJA. Additionally, this work was also supported by grants 5G12MD007592 and 5U54MD007592 to the Border Biomedical Research Center (BBRC) at UTEP from the National Institute on Minority Health and Health Disparities, a component of the National Institutes of Health.

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  1. Laboratorio de Biotecnología I, Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Circuito Universitario s/n, Campus II, C. P. 31125, Chihuahua, Chih, México

    Sayuri Nakamura-Bencomo, Blanca Iglesias-Figueroa, Tania S. Siqueiros-Cendón, Edward A. Espinoza-Sánchez, Sigifredo Arévalo-Gallegos & Quintín Rascón-Cruz

  2. The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, The University of Texas at El Paso, 500 West University Avenue, El Paso, 79968-0519, TX, USA

    Denisse A. Gutierrez, Elisa Robles-Escajeda, Renato J. Aguilera & Armando Varela-Ramirez

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Nakamura-Bencomo, S., Gutierrez, D.A., Robles-Escajeda, E. et al. Recombinant human lactoferrin carrying humanized glycosylation exhibits antileukemia selective cytotoxicity, microfilament disruption, cell cycle arrest, and apoptosis activities. Invest New Drugs 39, 400–415 (2021). https://doi.org/10.1007/s10637-020-01020-2

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