Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells

Mahboubeh S Noori; John D O'Brien; Zachary J Champa; Sudhir P Deosarkar; Olivia L Lanier; Chunyan Qi; Monica M Burdick; Frank L Schwartz; Stephen C Bergmeier; Kelly D McCall; Douglas J Goetz

doi:10.1016/j.ejphar.2017.03.049

Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells

Eur J Pharmacol. 2017 May 15:803:130-137. doi: 10.1016/j.ejphar.2017.03.049. Epub 2017 Mar 23.

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
² Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA.
³ Interthyr Corporation, 121 Putnam Street, Marietta, OH 45750, USA.
⁴ Department of Specialty Medicine, Ohio University, Athens, OH 45701, USA; The Diabetes Institute, Ohio University, Athens, OH 45701, USA.
⁵ Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
⁶ Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Specialty Medicine, Ohio University, Athens, OH 45701, USA; The Diabetes Institute, Ohio University, Athens, OH 45701, USA.

Abstract

Inhibition of interleukin-6 (IL-6) holds significant promise as a therapeutic approach for triple negative breast cancer (TNBC). We previously reported that phenylmethimazole (C10) reduces IL-6 expression in several cancer cell lines. We have identified a more potent derivative of C10 termed COB-141. In the present work, we tested the hypothesis that C10 and COB-141 inhibit TNBC cell expressed IL-6 and investigated the potential for classical IL-6 pathway induced signaling within TNBC cells. A panel of TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-468) was used. Enzyme linked immunosorbent assays (ELISA) revealed that C10 and COB-141 inhibit MDA-MB-231 cell IL-6 secretion, with COB-141 being ~6.5 times more potent than C10. Therefore, the remainder of the study focused on COB-141 which inhibited IL-6 secretion, and was found, via quantitative real time polymerase chain reaction (QRT-PCR), to inhibit IL-6 mRNA in the TNBC panel. COB-141 had little, if any, effect on metabolic activity indicating that the IL-6 inhibition is not via a toxic effect. Flow cytometric analysis and QRT-PCR revealed that the TNBC cell lines do not express the IL-6 receptor (IL-6Rα). Trans-AM assays suggested that COB-141 exerts its inhibitory effect, at least in part, by reducing NF-κB (p65/p50) DNA binding. In summary, COB-141 is a potent inhibitor of TNBC cell expressed IL-6 and the inhibition does not appear to be due to non-specific toxicity. The TNBC cell lines do not have an intact classical IL-6 signaling pathway. COB-141's inhibitory effect may be due, at least in part, to reducing NF-κB (p65/p50) DNA binding.

Keywords: Breast cancer; Cytokine; Interleukin-6; Methimazole.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Gene Expression Regulation, Neoplastic / drug effects*
Humans
Interleukin-6 / metabolism*
Interleukin-8 / metabolism
Methimazole / analogs & derivatives*
Methimazole / chemistry
Methimazole / pharmacology
NF-kappa B p50 Subunit / metabolism
Thiazoles / chemistry*
Thiones / chemistry*
Thiones / pharmacology*
Transcription Factor RelA / metabolism
Triple Negative Breast Neoplasms / pathology*

Substances

Antineoplastic Agents
Interleukin-6
Interleukin-8
NF-kappa B p50 Subunit
Thiazoles
Thiones
Transcription Factor RelA
phenyl methimazole
Methimazole

Grants and funding

R15 GM110602/GM/NIGMS NIH HHS/United States