The antidepressant imipramine inhibits breast cancer growth by targeting estrogen receptor signaling and DNA repair events.
Breast cancer
DNA damage
DNA repair
Drug repurposing
Estrogen receptor
Imipramine
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
01 08 2022
01 08 2022
Historique:
received:
04
02
2022
revised:
11
04
2022
accepted:
28
04
2022
pubmed:
15
5
2022
medline:
7
6
2022
entrez:
14
5
2022
Statut:
ppublish
Résumé
Aberrant activities of various cell cycle and DNA repair proteins promote cancer growth and progression and render them resistant to therapies. Here, we demonstrate that the anti-depressant imipramine blocks growth of triple-negative (TNBC) and estrogen receptor-positive (ER+) breast cancers by inducing cell cycle arrest and by blocking heightened homologous recombination (HR) and non-homologous end joining-mediated (NHEJ) DNA repair activities. Our results reveal that imipramine inhibits the expression of several cell cycle- and DNA repair-associated proteins including E2F1, CDK1, Cyclin D1, and RAD51. In addition, we show that imipramine inhibits the growth of ER + breast cancers by inhibiting the estrogen receptor- α (ER-α) signaling. Our studies in preclinical mouse models and ex vivo explants from breast cancer patients show that imipramine sensitizes TNBC to the PARP inhibitor olaparib and endocrine resistant ER + breast cancer to anti-estrogens. Our studies suggest that repurposing imipramine could enhance routine care for breast cancer patients. Based on these results, we designed an ongoing clinical trial, where we are testing the efficacy of imipramine for treating patients with triple-negative and estrogen receptor-positive breast cancer. Since aberrant DNA repair activity is used by many cancers to survive and become resistant to therapy, imipramine could be used alone and/or with currently used drugs for treating many aggressive cancers.
Identifiants
pubmed: 35568265
pii: S0304-3835(22)00201-4
doi: 10.1016/j.canlet.2022.215717
pmc: PMC10313451
mid: NIHMS1821833
pii:
doi:
Substances chimiques
Antidepressive Agents
0
Receptors, Estrogen
0
Imipramine
OGG85SX4E4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
215717Subventions
Organisme : NCI NIH HHS
ID : R01 CA179120
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239227
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA148724
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA054174
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001120
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
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