Small-Molecule Natural Product Physachenolide C Potentiates Immunotherapy Efficacy by Targeting BET Proteins.
Animals
Antineoplastic Agents, Phytogenic
/ pharmacology
Apoptosis
Biological Products
/ pharmacology
Carcinoma, Renal Cell
/ drug therapy
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Proliferation
Drug Therapy, Combination
Female
Humans
Immunotherapy
/ methods
Interferon Inducers
/ pharmacology
Kidney Neoplasms
/ drug therapy
Male
Melanoma, Experimental
/ drug therapy
Mice
Mice, Inbred BALB C
Mice, Nude
Poly I-C
/ pharmacology
Transcription Factors
/ antagonists & inhibitors
Tumor Cells, Cultured
Withanolides
/ pharmacology
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 06 2021
15 06 2021
Historique:
received:
13
08
2020
revised:
10
02
2021
accepted:
08
04
2021
pubmed:
11
4
2021
medline:
15
12
2021
entrez:
10
4
2021
Statut:
ppublish
Résumé
Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product of the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that PCC was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of antiapoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a proapoptotic ripoptosome signaling complex. Administration of a combination of PCC and poly I:C in human M14 melanoma xenograft and a syngeneic B16 melanoma model provided significant therapeutic benefit as compared with individual agents. In addition, PCC enhanced melanoma cell death in response to activated human T cells
Identifiants
pubmed: 33837043
pii: 0008-5472.CAN-20-2634
doi: 10.1158/0008-5472.CAN-20-2634
pmc: PMC8802328
mid: NIHMS1695101
doi:
Substances chimiques
Antineoplastic Agents, Phytogenic
0
BRD4 protein, human
0
Biological Products
0
Cell Cycle Proteins
0
Interferon Inducers
0
Transcription Factors
0
Withanolides
0
physachenolide C
0
Poly I-C
O84C90HH2L
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3374-3386Subventions
Organisme : NCI NIH HHS
ID : SC1 CA182843
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES006694
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA163069
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023074
Pays : United States
Informations de copyright
©2021 American Association for Cancer Research.
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