Inhibition of FoxM1-Mediated DNA Repair by Imipramine Blue Suppresses Breast Cancer Growth and Metastasis

Abstract

Purpose The approaches aimed at inhibiting the ability of cancer cells to repair DNA strand breaks have emerged as promising targets for treating cancers. Here, we assessed the potential of imipramine blue (IB), a novel analogue of anti-depressant imipramine, to suppress breast cancer growth and metastasis by inhibiting the ability of breast cancer cells to repair DNA strand breaks by homologous recombination. Experimental Design The effect of IB on breast cancer growth and metastasis was assessed in vitro as well as in preclinical mouse models. Besides, the therapeutic efficacy and safety of IB was determined in ex-vivo explants from breast cancer patients. The mechanism of action of IB was evaluated by performing gene expression, drug-protein interaction, cell cycle and DNA repair studies. Results We show that the systemic delivery of IB using nanoparticle-based delivery approach suppressed breast cancer growth and metastasis without inducing toxicity in preclinical mouse models. Using ex-vivo explants from breast cancer patients, we demonstrated that IB inhibited breast cancer growth without affecting normal mammary epithelial cells. Furthermore, our mechanistic studies revealed that IB may interact and inhibit the activity of proto-oncogene FoxM1 and associated signaling that play critical roles in homologous recombination-mediated DNA repair. Conclusions These findings highlight the potential of IB to be applied as a safe regimen for treating breast cancer patients. Given that FoxM1 is an established therapeutic target for several cancers, the identification of a compound that inhibits FoxM1 and FoxM1-mediated DNA repair has immense translational potential for treating many aggressive cancers.

microRNA‐216b inhibits cell proliferation and migration in human melanoma by targeting FOXM1 in vitro and in vivo

“…As a member of an evolutionarily conserved family of transcription factors characterized by a DNA-binding domain called the Forkhead Box (Kalin et al, 2011), FOXM1 is also known as a representative proliferationassociated transcription factor, such as prostate cancer (Lokody, 2014), hepatocellular carcinoma (Yamashita et al, 2014), glioblastoma (Gong et al, 2015), and bladder cancer (Kim et al, 2014). The overexpression of FOXM1 observed that FOXM1 is associated with an aggressive phenotype and poor prognosis in patients with breast cancer (Rajamanickam et al, 2016). Furthermore, Balli et al (2013) reported that FOXM1 could promote the epithelialmesenchymal transition (EMT) of lung cancer cells through stimulating the transcription of Slug.…”

Aberrant DNA Double-strand Break Repair Threads in Breast Carcinoma: Orchestrating Genomic Insult Survival

“…To achieve better outcomes in breast carcinoma, DNA repair protein inhibition strategies are highly necessary. In the same direction, imipramine blue, which is an inhibitor of forkhead box protein M1 (FOXM1)-mediated HR DNA repair pathways, inhibits breast cancer growth 42. Ataxia telangiectasia and Rad3-related kinase, a member of the phosphatidylinositol-3-related protein kinases, is the basis for strategies to silence several types of cancer because these kinases are responsible for the DNA damage response during chemotherapy and radiation therapy in cancer patients 43.…”

High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania

“…Apart from this, imipramine compound has also shown a better result for the treatment of patients with spontaneous panic attack as compared to placebo [30]. Recently, Imipramine blue, a unique analogue of imipramine, an anti-depressant drug, has shown its role in suppression of breast cancer and metastasis by inhibiting the homologous recombination mediated DNA repair mechanism of breast cancer cells [31]. The severity of visceral leishmaniasis in endemic zone of Indian subcontinent and lack of efficacious drug urge an urgent requirement of an antileishmanial drug with good efficacy and minimum toxicity.…”