Abstract 4716: Dimethyl fumarate impairs breast cancer growth and inhibits the nuclear factor κB pathway in breast cancer cells by covalent modification of p65

Abstract

Despite major advances in breast cancer treatment, successful therapy outcome is limited to early detection of cancer at the primary organ. Therapy options for aggressive, advanced stage, metastatic and recurring cancers are limited and this translates to poor patient outcome contributing to over 40,000 deaths each year in the United States. A key underlying factor of aggressive breast cancers is activation of the inflammatory nuclear factor κB (NFκB) pathway because it promotes numerous phenotypes such as cell survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy. Therefore, adding an anti-inflammatory/anti-NFκB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a mono- or adjuvant therapy. One option is Tecfidera® (dimethyl fumarate, DMF), the anti-inflammatory drug already in clinical use for multiple schlerosis. DMF is neuroprotective and is proposed to act via inhibition of the NFκB and activation of Nrf2 pathway. Most importantly, DMF has a proven safety in humans. This makes DMF an attractive candidate for NFκB inhibition in breast cancer therapy. Moreover, its therapeutic potential in treating breast cancer has yet to be explored. We find that DMF inhibits proliferation of breast cancer cells in vitro. In addition, DMF abrogates mammosphere formation, a functional measure of cancer stem cell (CSC) properties. This prompted us to examine its activity in a murine breast cancer xenograft model. We find that DMF (30mg/kg daily) significantly impairs MDA-MB-231 tumor growth in athymic nude mice. As an anti-inflammatory agent, we show that DMF effectively blocks NFκB activity in multiple breast cancer cell lines. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity, but has no effect on upstream proteins in the NFκB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFκB activity. Also, the cell permeable thiol, N-acetyl L-cysteine, reverses DMF's inhibition of the NFκB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF directly interacts with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality, and found that DMF covalently modifies p65 at the cysteine 38 residue. Altogether, these results establish DMF as a safe and effective NFκB inhibitor in breast cancer cells and elucidate its mechanism of action. These in addition to DMF's anti-tumor activity support the advancement of DMF as a therapeutic option to treat aggressive breast cancers in the clinic. Citation Format: Irida Kastrati, Marton I. Siklos, Esther L. Calderon-Gierszal, Gregory R. J. Thatcher, Jonna Frasor. Dimethyl fumarate impairs breast cancer growth and inhibits the nuclear factor κB pathway in breast cancer cells by covalent modification of p65. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4716.

Dimethyl Fumarate Abrogates Growth and Metastasis of Hepatocellular Carcinoma by Regulating NRF2/Bcl-XL Axis and Synergizes with Sorafenib

“…DMF has been demonstrated promising in the treatment of psoriasis and multiple sclerosis treatment [21][22][23]. A review of the literature indicated that DMF exerts multiple pharmacological effects, including anti-in ammatory [24,25], immunomodulatory [26,27] and antineoplastic effects [28][29][30][31] in different cell types. Despite these promising results, the mechanisms underlying the anticancer action of dimethyl fumarate are not fully understood, and the cellular targets of DMF in HCC cells remain unidenti ed.…”

The Effect of NF-κB Deactivation on Cancer Cell Response to ALA Mediated Photodynamic Therapy

“…A number of molecular or immunological factors have been investigated to explore their potency to sensitize breast cancer cells [24][25][26][27] alongside other cancers [28,29] for therapeutic agents. Many researchers indicated the ability of DMF to inhibit NF-κB in many types of cancers and tumors [30,31]. The current work aims to explore the combination of PDT and DMF for NF-kB inhibition as a novel strategy against triple negative breast cancer, as both treatments are already clinically approved therapies in human patients.…”