Water extract of sporoderm-broken spores of Ganoderma lucidum enhanced pd-l1 antibody efficiency through downregulation and relieved complications of pd-l1 monoclonal antibody

Autor: Yuxiang Zhang, Hang Su, Wenkan Zhang, Jiahong Meng, Weiqi Yan, Tuoyu Di, Jiaming He, Yiying Qi, Guoqi Li
Rok vydání: 2020
Předmět:
0301 basic medicine
STAT3 Transcription Factor
Reishi
Cell
transcription-factor regulation
Down-Regulation
Bone Neoplasms
RM1-950
programmed cell death-ligand 1
B7-H1 Antigen
03 medical and health sciences
Mice
0302 clinical medicine
Downregulation and upregulation
In vivo
Cell Movement
Cell Line
Tumor
medicine
Animals
signal transduction and transcriptional activators
STAT3
Cell Proliferation
Pharmacology
Mice
Inbred BALB C
Osteosarcoma
biology
phosphorylation
Chemistry
sporoderm-broken spores of Ganoderma lucidum water extract
Antibodies
Monoclonal
General Medicine
Spores
Fungal
medicine.disease
Xenograft Model Antitumor Assays
Immune checkpoint
030104 developmental biology
medicine.anatomical_structure
Apoptosis
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
Therapeutics. Pharmacology
Signal transduction
Zdroj: Biomedicine & Pharmacotherapy, Vol 131, Iss, Pp 110541-(2020)
ISSN: 1950-6007
Popis: Purpose Osteosarcoma is a malignant musculoskeletal tumor with early metastasis and a poor prognosis, especially in adolescents. Ganoderma lucidum (Leyss. Ex Fr.) Karst (G. lucidum), a traditional East Asian medicine, has been reported to play a critical role in antitumor and immunomodulatory activity. The aim of this study was to investigate the effects and molecular mechanisms of water extract of sporoderm-broken spores of G. lucidum (BSGWE) on osteosarcoma PD-L1 (programmed cell death-ligand 1) transcriptional regulation, efficacy enhancement, and side effect remission. Methods The antitumor effects on cell proliferation of BSGWE in osteosarcoma cells were detected by apoptosis flow cytometry, and the migration ability of HOS and K7M2 cells were evaluated by cell scratch assay. Potential signaling regulation of PD-L1 was detected by western blotting. To confirm the signaling pathway of BSGWE-related PD-L1 downregulation, a pho-STAT3 turnover experiment was carried out. Colivelin was administered as a pho-STAT3 activator to rescue the BSGWE-induced PD-L1 inhibition. To further study in vivo signaling, in a Balb/c osteosarcoma allograft model, tumor volume was measured using an in vivo bioluminescence imaging system. The body weight curve and tumor volume curve were analyzed to reveal the remission effects of BSGWE on PD-L1 antibody-related body weight loss and its immunomodulatory effects on the osteosarcoma and spleen. The PD-L1 expression level and expression of related transcription-factor pho-STAT3 in tumor cells and spleens were assessed by IHC analysis. Results BSGWE suppressed the proliferation and migration of osteosarcoma cells in vitro via induction of apoptosis. In addition, BSGWE downregulated PD-L1 expression and related STAT3 (signal transducers and activators of transcription) phosphorylation levels in a dose-dependent manner. Western blotting and qRT-PCR assay revealed that BSGWE downregulated PD-L1 expression by inhibiting STAT3 phosphorylation. A turnover experiment showed that colivelin administration could rescue PD-L1 inhibition via pho-STAT3 activation. BSGWE not only downregulated PD-L1 expression via the STAT3 pathway in an allograft Balb/c mouse model, but also relieved complications including weight loss and spleen atrophy in a mouse monoclonal antibody therapy model on the basis of its traditional advantages in immune enhancement. Conclusion BSGWE downregulated PD-L1 expression via pho-STAT3 inhibition of protein and RNA levels. BSGWE enhanced PD-L1 antibody efficacy via phosphorylated STAT3 downregulation in vitro and in vivo. BSGWE also relieved complications of weight loss and spleen atrophy in a murine allograft osteosarcoma immune checkpoint blockade therapy model.
Databáze: OpenAIRE
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