Small molecule BKM1972 inhibits human prostate cancer growth and overcomes docetaxel resistance in intraosseous models.
ATP Binding Cassette Transporter, Subfamily B
/ genetics
Animals
Antineoplastic Agents
/ pharmacology
Bone Neoplasms
/ drug therapy
Bradykinin Receptor Antagonists
/ pharmacology
Cell Line, Tumor
Cell Proliferation
/ drug effects
Docetaxel
/ pharmacology
Drug Resistance, Neoplasm
Humans
Male
Mice, Nude
Molecular Targeted Therapy
Organophosphonates
/ pharmacology
Phosphorylation
Prostatic Neoplasms
/ drug therapy
STAT3 Transcription Factor
/ metabolism
Signal Transduction
/ drug effects
Survivin
/ genetics
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
Bone metastasis
Chemoresistance
Preclinical model
Prostate cancer
Small-molecule therapy
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
01 04 2019
01 04 2019
Historique:
received:
12
09
2018
revised:
15
12
2018
accepted:
07
01
2019
pubmed:
21
1
2019
medline:
18
12
2019
entrez:
21
1
2019
Statut:
ppublish
Résumé
Bone metastasis is a major cause of prostate cancer (PCa) mortality. Although docetaxel chemotherapy initially extends patients' survival, in most cases PCa becomes chemoresistant and eventually progresses without a cure. In this study, we developed a novel small-molecule compound BKM1972, which exhibited potent in vitro cytotoxicity in PCa and other cancer cells regardless of their differences in chemo-responsiveness. Mechanistic studies demonstrated that BKM1972 effectively inhibited the expression of anti-apoptotic protein survivin and membrane-bound efflux pump ATP binding cassette B 1 (ABCB1, p-glycoprotein), presumably via signal transducer and activator of transcription 3 (Stat3). BKM1972 was well tolerated in mice and as a monotherapy, significantly inhibited the intraosseous growth of chemosensitive and chemoresistant PCa cells. These results indicate that BKM1972 is a promising small-molecule lead to treat PCa bone metastasis and overcome docetaxel resistance.
Identifiants
pubmed: 30660650
pii: S0304-3835(19)30022-9
doi: 10.1016/j.canlet.2019.01.010
pmc: PMC6361683
mid: NIHMS1519046
pii:
doi:
Substances chimiques
ABCB1 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
Antineoplastic Agents
0
BIRC5 protein, human
0
Bradykinin Receptor Antagonists
0
Organophosphonates
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Survivin
0
Docetaxel
15H5577CQD
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
62-72Subventions
Organisme : NCI NIH HHS
ID : R41 CA217491
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA164612
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA206725
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA256058
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA186498
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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