Repurposing Anti-Depressant Imipramine For Treating Breast Cancers

About 1 in 8 women will develop invasive breast cancer during their life time and more than 41,000 women die every year in the United States alone. Most of these deaths are attributed to relapse, distant metastasis and therapy resistance. For example, despite initial response to therapy, a significant proportion of ER+ BCs become therapy resistant and progress to incurable metastases. Similarly, TNBCs, which is highly aggressive and are more likely to occur in Hispanic and black women, have higher propensity to relapse and contribute to disproportionate number of deaths. Unfortunately, the patients who do survive, have reduced quality of life due to the chemotherapy-associated toxicity. One mechanism that helps BCs to survive and become therapy-resistant is their unique ability to keep repairing their DNA. The aim of this study was to identify and test whether any FDA-approved non-cancer drug/s can block DNA repair ability and consequently growth of BC cells. Treatment of BC cells with a set of FDA approved drugs showed that antidepressants imipramine can inhibit the BC cell growth. Imipramine treatment significantly reduced the short and long-term viability of TNBC and ER+ breast cancer cells. Further, imipramine treatment inhibited the migration and invasion of breast cancer cells. Systemic delivery of imipramine suppressed the breast cancer cells growth in orthotopic mouse xenograft model. Our results revealed that imipramine treatment induced G1/S cell cycle arrest and apoptosis in breast cancer cells. Importantly, imipramine blocked the DNA repair capacity of BC cells by inhibiting the expression of DNA repair proteins including FOXM1 and RAAD51. Notably, imipramine treatment improved the efficacy of the PARP inhibitor “olapraib” in TNBC and sensitized the tamoxifen response in tamoxifen resistant ER+ breast cancer cells. Our results suggest that imipramine can be used as a single or therapeutic adjuvant for treating therapy sensitive and therapy resistant breast cancers. Based on these results, we are currently conducting a clinical trial to test the therapeutic efficacy of imipramine for treating breast cancer patients (https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2017 01937r 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-25.