Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells.
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.
Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
Mahboubeh S
MS
Noori
Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA.
John D
JD
O'Brien
Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA.
Zachary J
ZJ
Champa
Interthyr Corporation, 121 Putnam Street, Marietta, OH 45750, USA.
Sudhir P
SP
Deosarkar
Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA.
Olivia L
OL
Lanier
Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA.
Chunyan
C
Qi
Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA.
Monica M
MM
Burdick
Department of Specialty Medicine, Ohio University, Athens, OH 45701, USA; The Diabetes Institute, Ohio University, Athens, OH 45701, USA.
Frank L
FL
Schwartz
Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA; Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
Stephen C
SC
Bergmeier
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.
Kelly D
KD
McCall
Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH 45701, USA.
Douglas J
DJ
Goetz
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D008713:Methimazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry*; D013871:Thiones / Q000737:chemistry* / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; D015850:Interleukin-6; D016209:Interleukin-8; D052002:NF-kappa B p50 Subunit; D013844:Thiazoles; D013871:Thiones; D051996:Transcription Factor RelA; C489637:phenyl methimazole; D008713:Methimazole
Breast cancer; Cytokine; Interleukin-6; Methimazole