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16.10.2020 | PRECLINICAL STUDIES

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

verfasst von: Sayuri Nakamura-Bencomo, Denisse A. Gutierrez, Elisa Robles-Escajeda, Blanca Iglesias-Figueroa, Tania S. Siqueiros-Cendón, Edward A. Espinoza-Sánchez, Sigifredo Arévalo-Gallegos, Renato J. Aguilera, Quintín Rascón-Cruz, Armando Varela-Ramirez

Erschienen in: Investigational New Drugs | Ausgabe 2/2021

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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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Titel: Recombinant human lactoferrin carrying humanized glycosylation exhibits antileukemia selective cytotoxicity, microfilament disruption, cell cycle arrest, and apoptosis activities
verfasst von: Sayuri Nakamura-Bencomo
Denisse A. Gutierrez
Elisa Robles-Escajeda
Blanca Iglesias-Figueroa
Tania S. Siqueiros-Cendón
Edward A. Espinoza-Sánchez
Sigifredo Arévalo-Gallegos
Renato J. Aguilera
Quintín Rascón-Cruz
Armando Varela-Ramirez
Publikationsdatum: 16.10.2020
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 2/2021
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-020-01020-2

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

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

Summary

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Springer Medizin

Summary

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