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Repositioning Azelnidipine as a Dual Inhibitor Targeting CD47/SIRPα and TIGIT/PVR Pathways for Cancer Immuno-Therapy
- Source :
- Biomolecules, Vol 11, Iss 706, p 706 (2021), Biomolecules, Volume 11, Issue 5
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8+ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8+ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy.
- Subjects :
- 0301 basic medicine
Dihydropyridines
T-Lymphocytes
medicine.medical_treatment
Azelnidipine
CD47/SIRPα
Biochemistry
Mice
azelnidipine
0302 clinical medicine
Cancer immunotherapy
Cricetinae
Neoplasms
Molecular Targeted Therapy
Receptors, Immunologic
Mice, Inbred BALB C
medicine.diagnostic_test
Chemistry
small molecule inhibitor
Calcium Channel Blockers
Acquired immune system
QR1-502
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
030220 oncology & carcinogenesis
Receptors, Virus
Immunotherapy
Azetidinecarboxylic Acid
medicine.drug
T cell
CD47 Antigen
Microbiology
Article
Flow cytometry
03 medical and health sciences
Immune system
TIGIT
Cell Line, Tumor
medicine
Animals
Humans
Molecular Biology
cancer immunotherapy
CD47
Drug Repositioning
drug-repositioning
Immunity, Innate
Mice, Inbred C57BL
Disease Models, Animal
TIGIT/PVR
030104 developmental biology
Cancer research
Subjects
Details
- Language :
- English
- Volume :
- 11
- Issue :
- 706
- Database :
- OpenAIRE
- Journal :
- Biomolecules
- Accession number :
- edsair.doi.dedup.....f808e2d4b7840ac3abfb5d2a55d17120