Compensatory combination of romidepsin with gemcitabine and cisplatin to effectively and safely control urothelial carcinoma.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Apoptosis
/ drug effects
Carcinoma, Transitional Cell
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cisplatin
/ pharmacology
Deoxycytidine
/ analogs & derivatives
Depsipeptides
/ pharmacology
Humans
MAP Kinase Signaling System
/ drug effects
Mice
Neoplasm Recurrence, Local
/ drug therapy
Reactive Oxygen Species
/ metabolism
Urinary Bladder Neoplasms
/ drug therapy
Urothelium
/ drug effects
Xenograft Model Antitumor Assays
Gemcitabine
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
27
11
2019
accepted:
15
04
2020
revised:
26
03
2020
pubmed:
12
5
2020
medline:
20
2
2021
entrez:
12
5
2020
Statut:
ppublish
Résumé
Human urothelial carcinoma (UC) has a high tendency to recur and progress to life-threatening advanced diseases. Advanced therapeutic regimens are needed to control UC development and recurrence. We pursued in vitro and in vivo studies to understand the ability of a triple combination of gemcitabine, romidepsin, and cisplatin (Gem+Rom+Cis) to modulate signalling pathways, cell death, drug resistance, and tumour development. Our studies verified the ability of Gem+Rom+Cis to synergistically induce apoptotic cell death and reduce drug resistance in various UC cells. The ERK pathway and reactive oxygen species (ROS) played essential roles in mediating Gem+Rom+Cis-induced caspase activation, DNA oxidation and damage, glutathione reduction, and unfolded protein response. Gem+Rom+Cis preferentially induced death and reduced drug resistance in oncogenic H-Ras-expressing UC vs. counterpart cells that was associated with transcriptomic profiles related to ROS, cell death, and drug resistance. Our studies also verified the efficacy and safety of the Gem plus Rom+Cis regimen in controlling UC cell-derived xenograft tumour development and resistance. More than 80% of UCs are associated with aberrant Ras-ERK pathway. Thus the compensatory combination of Rom with Gem and Cis should be seriously considered as an advanced regimen for treating advanced UCs, especially Ras-ERK-activated UCs.
Sections du résumé
BACKGROUND
Human urothelial carcinoma (UC) has a high tendency to recur and progress to life-threatening advanced diseases. Advanced therapeutic regimens are needed to control UC development and recurrence.
METHODS
We pursued in vitro and in vivo studies to understand the ability of a triple combination of gemcitabine, romidepsin, and cisplatin (Gem+Rom+Cis) to modulate signalling pathways, cell death, drug resistance, and tumour development.
RESULTS
Our studies verified the ability of Gem+Rom+Cis to synergistically induce apoptotic cell death and reduce drug resistance in various UC cells. The ERK pathway and reactive oxygen species (ROS) played essential roles in mediating Gem+Rom+Cis-induced caspase activation, DNA oxidation and damage, glutathione reduction, and unfolded protein response. Gem+Rom+Cis preferentially induced death and reduced drug resistance in oncogenic H-Ras-expressing UC vs. counterpart cells that was associated with transcriptomic profiles related to ROS, cell death, and drug resistance. Our studies also verified the efficacy and safety of the Gem plus Rom+Cis regimen in controlling UC cell-derived xenograft tumour development and resistance.
CONCLUSIONS
More than 80% of UCs are associated with aberrant Ras-ERK pathway. Thus the compensatory combination of Rom with Gem and Cis should be seriously considered as an advanced regimen for treating advanced UCs, especially Ras-ERK-activated UCs.
Identifiants
pubmed: 32390005
doi: 10.1038/s41416-020-0877-8
pii: 10.1038/s41416-020-0877-8
pmc: PMC7374627
doi:
Substances chimiques
Depsipeptides
0
Reactive Oxygen Species
0
Deoxycytidine
0W860991D6
romidepsin
CX3T89XQBK
Cisplatin
Q20Q21Q62J
Gemcitabine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
226-239Subventions
Organisme : NCI NIH HHS
ID : R21 CA177834
Pays : United States
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : CA177834
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