Cargando…

Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells

BACKGROUND: Daunorubicin is a traditional chemotherapeutic agent that plays a pivotal role in leukemia therapy. However, the dose-related toxicity remains a considerable challenge. The apoptosis-regulating gene, PDCD5, is downregulated in various tumors, including leukemias, and may provide a potent...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Ya-Lan, Yao, Qiu-Mei, Zhou, Jiao, Chang, Yan, Li, Jin-Lan, Wang, Ya-Zhe, Wu, Hong-Ping, Chen, Yu-Hong, Liu, Yan-Rong, Huang, Xiao-Jun, Ruan, Guo-Rui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112794/
https://www.ncbi.nlm.nih.gov/pubmed/30197523
http://dx.doi.org/10.2147/OTT.S167868
_version_ 1783350905444237312
author Zhou, Ya-Lan
Yao, Qiu-Mei
Zhou, Jiao
Chang, Yan
Li, Jin-Lan
Wang, Ya-Zhe
Wu, Hong-Ping
Chen, Yu-Hong
Liu, Yan-Rong
Huang, Xiao-Jun
Ruan, Guo-Rui
author_facet Zhou, Ya-Lan
Yao, Qiu-Mei
Zhou, Jiao
Chang, Yan
Li, Jin-Lan
Wang, Ya-Zhe
Wu, Hong-Ping
Chen, Yu-Hong
Liu, Yan-Rong
Huang, Xiao-Jun
Ruan, Guo-Rui
author_sort Zhou, Ya-Lan
collection PubMed
description BACKGROUND: Daunorubicin is a traditional chemotherapeutic agent that plays a pivotal role in leukemia therapy. However, the dose-related toxicity remains a considerable challenge. The apoptosis-regulating gene, PDCD5, is downregulated in various tumors, including leukemias, and may provide a potential target for the diagnosis and treatment of leukemia. The purpose of this study was to construct a triple-regulated oncolytic adenovirus carrying a PDCD5 gene expression cassette (SG611-PDCD5) and explore the combined antitumor efficacy of SG611-PDCD5 in combination with low dose daunorubicin on leukemic cells. MATERIALS AND METHODS: A variety of leukemic cell lines, including K562, MEG-01, KG-1a, HL-60, SUP-B15, and BV-173, were cultured according to the providers’ instructions. The insertion and orientation of all recombined plasmids were confirmed by restriction enzyme digestion and PCR. The tumor-selective replication of the constructed conditionally replicating SG611-PDCD5 and its antitumor efficacy in combination with daunorubicin were characterized in leukemic cell lines in vitro and in a nude mouse xenograft model. Cell viability was detected using cell-counting kit-8. Apoptosis was detected in whole living cells using flow cytometry and in paraffin-embedded tumor tissues using a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: The triple-regulated CRAd carrying SG611-PDCD5 and nude mouse xenograft models of K562 cells were successfully constructed. In vitro treatment with SG611-PDCD5 in combination with low-dose daunorubicin elicited more potent anti-proliferative and proapoptotic effects in leukemic cells in a dose-dependent manner. The Chou-Talalay analysis revealed synergistic anti-proliferative effects in all of the above cell lines. In the nude mice xenograft model, the tumor size in the control, daunorubicin, SG611-PDCD5, and combined treatment groups on day 10 were 170.1±47.8, 111.9±81.1, 60.7±12.3, and 33.2±17.5 mm(3), respectively (all P<0.05). The results of the TUNEL assay showed significantly more apoptotic cells in the SG611-PDCD5 plus daunorubicin group than in the SG611-PDCD5 or daunorubicin groups alone (25±0.82, 12.5±2.27, and 7.8±2.67 apoptotic cells/field, respectively) (P<0.05). CONCLUSION: The findings suggest that combined treatment with SG611-PDCD5 and daunorubicin may be a promising strategy for enhancing chemosensitivity and thus lowering the dose-related toxicity of daunorubicin in leukemia therapy.
format Online
Article
Text
id pubmed-6112794
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Dove Medical Press
record_format MEDLINE/PubMed
spelling pubmed-61127942018-09-07 Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells Zhou, Ya-Lan Yao, Qiu-Mei Zhou, Jiao Chang, Yan Li, Jin-Lan Wang, Ya-Zhe Wu, Hong-Ping Chen, Yu-Hong Liu, Yan-Rong Huang, Xiao-Jun Ruan, Guo-Rui Onco Targets Ther Original Research BACKGROUND: Daunorubicin is a traditional chemotherapeutic agent that plays a pivotal role in leukemia therapy. However, the dose-related toxicity remains a considerable challenge. The apoptosis-regulating gene, PDCD5, is downregulated in various tumors, including leukemias, and may provide a potential target for the diagnosis and treatment of leukemia. The purpose of this study was to construct a triple-regulated oncolytic adenovirus carrying a PDCD5 gene expression cassette (SG611-PDCD5) and explore the combined antitumor efficacy of SG611-PDCD5 in combination with low dose daunorubicin on leukemic cells. MATERIALS AND METHODS: A variety of leukemic cell lines, including K562, MEG-01, KG-1a, HL-60, SUP-B15, and BV-173, were cultured according to the providers’ instructions. The insertion and orientation of all recombined plasmids were confirmed by restriction enzyme digestion and PCR. The tumor-selective replication of the constructed conditionally replicating SG611-PDCD5 and its antitumor efficacy in combination with daunorubicin were characterized in leukemic cell lines in vitro and in a nude mouse xenograft model. Cell viability was detected using cell-counting kit-8. Apoptosis was detected in whole living cells using flow cytometry and in paraffin-embedded tumor tissues using a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: The triple-regulated CRAd carrying SG611-PDCD5 and nude mouse xenograft models of K562 cells were successfully constructed. In vitro treatment with SG611-PDCD5 in combination with low-dose daunorubicin elicited more potent anti-proliferative and proapoptotic effects in leukemic cells in a dose-dependent manner. The Chou-Talalay analysis revealed synergistic anti-proliferative effects in all of the above cell lines. In the nude mice xenograft model, the tumor size in the control, daunorubicin, SG611-PDCD5, and combined treatment groups on day 10 were 170.1±47.8, 111.9±81.1, 60.7±12.3, and 33.2±17.5 mm(3), respectively (all P<0.05). The results of the TUNEL assay showed significantly more apoptotic cells in the SG611-PDCD5 plus daunorubicin group than in the SG611-PDCD5 or daunorubicin groups alone (25±0.82, 12.5±2.27, and 7.8±2.67 apoptotic cells/field, respectively) (P<0.05). CONCLUSION: The findings suggest that combined treatment with SG611-PDCD5 and daunorubicin may be a promising strategy for enhancing chemosensitivity and thus lowering the dose-related toxicity of daunorubicin in leukemia therapy. Dove Medical Press 2018-08-23 /pmc/articles/PMC6112794/ /pubmed/30197523 http://dx.doi.org/10.2147/OTT.S167868 Text en © 2018 Zhou et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Zhou, Ya-Lan
Yao, Qiu-Mei
Zhou, Jiao
Chang, Yan
Li, Jin-Lan
Wang, Ya-Zhe
Wu, Hong-Ping
Chen, Yu-Hong
Liu, Yan-Rong
Huang, Xiao-Jun
Ruan, Guo-Rui
Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells
title Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells
title_full Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells
title_fullStr Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells
title_full_unstemmed Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells
title_short Synergistic antitumoral efficacy of a novel replicative adenovirus SG611-PDCD5 and daunorubicin in human leukemic cells
title_sort synergistic antitumoral efficacy of a novel replicative adenovirus sg611-pdcd5 and daunorubicin in human leukemic cells
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112794/
https://www.ncbi.nlm.nih.gov/pubmed/30197523
http://dx.doi.org/10.2147/OTT.S167868
work_keys_str_mv AT zhouyalan synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT yaoqiumei synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT zhoujiao synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT changyan synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT lijinlan synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT wangyazhe synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT wuhongping synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT chenyuhong synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT liuyanrong synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT huangxiaojun synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells
AT ruanguorui synergisticantitumoralefficacyofanovelreplicativeadenovirussg611pdcd5anddaunorubicininhumanleukemiccells