Abstract 1787: Imipramine blue: a novel NOX inhibitor as potent therapeutic agent to treat triple-negative breast cancers
Authors: Subapriya Rajamanickam, Panneerdoss Subbarayalu, Santhosh Timilsina, Michael T. Drake, Zhenze Zhao, Hung I Harry Chen, Yidong Chen, Jack L. Arbiser, Manjeet K K. Rao
Journal: Cancer Research (2015)

Abstract Breast cancer is the most common cancer in women and the second leading cause of cancer death in US. Triple-negative breast cancers (TNBC) are the most aggressive forms of breast cancer. Almost 60% of patients with TNBCs develop chemo-resistance, leading to early relapse and shorter survival. The family of NADPH oxidases (NOX) enzymes is more abundant source of reactive oxygen species, which generally over expressed in a wide range of cancers including breast cancer. Over expression of NOX family of proteins in the tumor cells and stroma results in the activation of several intracellular pathways that promotes neoplastic transformation. Moreover, NOX is an important metabolic enzyme that plays a critical role in supporting increased glycolysis in cancer cells by generating NAD+, a substrate for one of the key glycolytic reactions. The constitutive upregulation of glycolysis is thought to confer significant growth advantage to cancer cells leading to uncontrolled proliferation and increased invasion. This is especially true for TNBC that shows a strong association with the Warburg effect. Herein we evaluated first time the role of imipramine blue (IB), a NOX inhibitor and a derivative of the FDA approved antidepressant imipramine in TNBC cells growth and progression. Our results demonstrated that imipramine blue inhibits TNBC, MDA-MB-231, MDA-MB-468 and Bt-549 cells growth without affecting normal mammary epithelial (MCF-10A) cells. Notably, our studies revealed that imipramine blue targets multiple NOX family members, which are highly expressed in breast tumors when compared to adjacent normal tissue. Imipramine blue treatment also reduced migration and invasion and inhibited the self-renewal capability of MDA-MB-231 cells. Importantly, imipramine blue treatment significantly reduced experimental lung metastasis of MDA-MB-231 cells in athymic nude mice without induce apparent toxicity. Our gene microarray results further showed that IB treatment significantly altered an array of genes, including FOXM1, Aurora kinase A (AURAK) and Polo-like kinase 1 (PLK1), which play important roles in cancer growth and progression as well as in mediating sensitivity/resistance of paclitaxel (PTX), a chemotherapy drug that is routinely used as a first line treatment for breast cancer patients. Taken together, our findings propose NOX inhibitor imipramine blue as a novel therapeutic agent with less toxicity to treat triple negative breast cancers. Citation Format: Subapriya Rajamanickam, Panneerdoss Subbarayalu, Santhosh Timilsina, Michael T. Drake, Zhenze Zhao, Hung I Harry Chen, Yidong Chen, Jack L. Arbiser, Manjeet K K. Rao. Imipramine blue: a novel NOX inhibitor as potent therapeutic agent to treat triple-negative breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1787. doi:10.1158/1538-7445.AM2015-1787