TY - JOUR
T1 - The antidepressant imipramine inhibits breast cancer growth by targeting estrogen receptor signaling and DNA repair events
AU - Timilsina, Santosh
AU - Rajamanickam, Subapriya
AU - Rao, Arhan
AU - Subbarayalu, Panneerdoss
AU - Nirzhor, Saif
AU - Abdelfattah, Nourhan
AU - Viswanadhapalli, Suryavathi
AU - Chen, Yidong
AU - Jatoi, Ismail
AU - Brenner, Andrew
AU - Rao, Manjeet K.
AU - Vadlamudi, Ratna
AU - Kaklamani, Virginia
N1 - Funding Information:
MKRao is supported by NIH (NCI) Grants R01CA179120-01A1 and R01CA239227-01A1 and by CPRIT grant RP200110 . Y Chen is supported by CPRIT Core Grant RP16073 . They also are both supported by NCI P30 grant CA054174 . S Timilsina is supported by T32 CA148724.
Funding Information:
We thank the UTHSCSA Genome Sequencing and GCCRI Bioinformatics Core facilities for performing RNA sequencing and bioinformatics analysis, respectively. We thank Drs. Maria Jasin and Jeremy Stark for providing DR-GFP integrated U2OS cells and the pCAGGS vector with ISceI/GFP. We thank Dr. Alexander Bishop for providing reagents and antibodies. We thank Daniel Robledo of the Greehey Children's Cancer Research Institute Histology Core for his help with sample processing and immunohistochemical staining. We thank Karla Gorena, Sebastian Montagnino, and Catherine Davis from the UT Health San Antonio(UTHSA) Flow Cytometry Shared Resource Facility for their help in performing flow cytometry and data analyses. UTHSA Flow Cytometry Shared Resource Facility is supported by NIH-NCI P30 CA054174-20 (CTRC at UT Health), and UL1 TR001120 (CTSA grant). We thank Karen P. Klein (Clarus Editorial Services; [ 8 ] for editing.
Publisher Copyright:
© 2022 The Authors
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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.
AB - 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.
KW - Breast cancer
KW - DNA damage
KW - DNA repair
KW - Drug repurposing
KW - Estrogen receptor
KW - Imipramine
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UR - http://www.scopus.com/inward/citedby.url?scp=85130532575&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2022.215717
DO - 10.1016/j.canlet.2022.215717
M3 - Article
C2 - 35568265
AN - SCOPUS:85130532575
SN - 0304-3835
VL - 540
JO - Cancer Letters
JF - Cancer Letters
M1 - 215717
ER -