Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression.
ATP Binding Cassette Transporter, Subfamily B
/ genetics
Animals
Antibiotics, Antineoplastic
/ pharmacology
Apoptosis
/ drug effects
Bone Neoplasms
/ drug therapy
Cell Line, Tumor
Doxorubicin
/ pharmacology
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Oncolytic Virotherapy
/ methods
Osteosarcoma
/ drug therapy
Tumor Suppressor Protein p53
/ genetics
Xenograft Model Antitumor Assays
Chemoresistance
MDR1
Oncolytic adenovirus
Osteosarcoma
p53
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
17
12
2020
accepted:
31
05
2021
pubmed:
12
6
2021
medline:
18
11
2021
entrez:
11
6
2021
Statut:
ppublish
Résumé
Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.
Sections du résumé
BACKGROUND
Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells.
MATERIALS AND METHODS
The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model.
RESULTS
DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model.
CONCLUSION
Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.
Identifiants
pubmed: 34114067
doi: 10.1007/s00280-021-04310-5
pii: 10.1007/s00280-021-04310-5
doi:
Substances chimiques
ABCB1 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
Antibiotics, Antineoplastic
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Doxorubicin
80168379AG
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
513-524Subventions
Organisme : The Japan Agency for Medical Research and Development
ID : 17ck0106285h001
Organisme : The Ministry of Education, Culture, Sports, Science, and Technology, Japan
ID : 25293238
Organisme : The Ministry of Education, Culture, Sports, Science, and Technology, Japan
ID : 16H05416
Organisme : The Ministry of Education, Culture, Sports, Science, and Technology, Japan
ID : 25293323
Organisme : The Ministry of Education, Culture, Sports, Science, and Technology, Japan
ID : 25462333
Organisme : The Ministry of Education, Culture, Sports, Science, and Technology, Japan
ID : 16K10862
Organisme : The Ministry of Education, Culture, Sports, Science, and Technology, Japan
ID : 15K10446
Organisme : The Ministry of Education, Culture, Sports, Science, and Technology, Japan
ID : 16K10596
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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