Imipramine mechanism of action in breast cancers

Model showing imipramine mechanism of action in breast cancers. Red boxes and lines indicate proteins/mechanisms that act to promote cancer growth and progression, while green boxes or lines represent proteins or pathways that inhibit breast cancer growth and progression. Based on our results, we propose that imipramine blocks breast cancer growth and progression by inhibiting cell cycle, DNA Repair, and ER-α signaling. We show that imipramine treatment leads to an increase in CDK inhibitors including p15, p21, and p27, which inhibit the activity of CDK4/6 and CDK2 (marked by X), consequently preventing the hyperphosphorylation and loss of activity of the RB protein. This leads to reduced E2F activity, reduced transcription of S phase genes, and increased G1/S cell cycle arrest. In addition to cell cycle progression, we show that imipramine treatment inhibits DNA Damage Response and DNA Repair pathway (marked by X), by inhibiting key players in the DNA Damage Response/DNA Repair pathway, including ATR, BRCA1, RAD51, and DNA-PKcs. We posit that reduced DNA repair leads to persistent/increased level of DNA damage and consequently apoptosis in imipramine-treated breast cancer cells. We propose that imipramine may block the growth and progression of ER + breast cancers by inhibiting ER-α signaling. Since effectors of DNA repair (such as FOXM1, RAD51 and BRCA1) and ER-a signaling functionally and physically crosstalk, our results suggest that imipramine inhibition of both DNA repair and ER-a signaling amplifies its anti-tumor effects on ER + breast cancers.

Publication

The antidepressant imipramine inhibits breast cancer growth by targeting estrogen receptor signaling and DNA repair events. (2023) Santosh Timilsina, et al. Cancer Lett. ;540:215717-215717. Figure: F6. All organisms Drosophila melanogaster Homo sapiens

Disease mentions