Inhibition of FoxM1-Mediated DNA repair by imipramine blue suppresses breast cancer growth and metastasis

Subapriya Rajamanickam, Subbarayalu Panneerdoss, Aparna Gorthi, Santosh Timilsina, Benjamin Onyeagucha, Dmytro Kovalskyy, Dmitri N Ivanov, Martha A. Hanes, Ratna K Vadlamudi, Yidong Chen, Alexander J Bishop, Jack L. Arbiser, Manjeet K Rao

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 antidepressant imipramine, to suppress breast cancer growth and metastasis by inhibiting the ability of breast cancer cells to repair DNA strand breaks by homologous recombination (HR). 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 HR-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.

Original languageEnglish (US)
Pages (from-to)3524-3536
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number14
DOIs
StatePublished - Jul 15 2016

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Imipramine
DNA Repair
Breast Neoplasms
Neoplasm Metastasis
Growth
DNA Breaks
Neoplasms
Recombinational DNA Repair
Cell Cycle Proteins
Proto-Oncogenes
Homologous Recombination
Drug Interactions
Nanoparticles
Antidepressive Agents
Breast
Research Design
Epithelial Cells
Safety
Gene Expression
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of FoxM1-Mediated DNA repair by imipramine blue suppresses breast cancer growth and metastasis. / Rajamanickam, Subapriya; Panneerdoss, Subbarayalu; Gorthi, Aparna; Timilsina, Santosh; Onyeagucha, Benjamin; Kovalskyy, Dmytro; Ivanov, Dmitri N; Hanes, Martha A.; Vadlamudi, Ratna K; Chen, Yidong; Bishop, Alexander J; Arbiser, Jack L.; Rao, Manjeet K.

In: Clinical Cancer Research, Vol. 22, No. 14, 15.07.2016, p. 3524-3536.

Research output: Contribution to journalArticle

Rajamanickam S, Panneerdoss S, Gorthi A, Timilsina S, Onyeagucha B, Kovalskyy D et al. Inhibition of FoxM1-Mediated DNA repair by imipramine blue suppresses breast cancer growth and metastasis. Clinical Cancer Research. 2016 Jul 15;22(14):3524-3536. https://doi.org/10.1158/1078-0432.CCR-15-2535
Rajamanickam, Subapriya ; Panneerdoss, Subbarayalu ; Gorthi, Aparna ; Timilsina, Santosh ; Onyeagucha, Benjamin ; Kovalskyy, Dmytro ; Ivanov, Dmitri N ; Hanes, Martha A. ; Vadlamudi, Ratna K ; Chen, Yidong ; Bishop, Alexander J ; Arbiser, Jack L. ; Rao, Manjeet K. / Inhibition of FoxM1-Mediated DNA repair by imipramine blue suppresses breast cancer growth and metastasis. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 14. pp. 3524-3536.
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