title: Doxycycline is an NF-κB inhibitor that induces apoptotic cell death in malignant T-cells.
abstract: Cutaneous T-cell Lymphoma (CTCL) is a rare non-Hodgkin's lymphoma that can affect the skin, blood, and lymph nodes, and can metastasize at late stages. Novel therapies that target all affected disease compartments and provide longer lasting responses while being safe are needed. One potential therapeutic target is NF-κB, a regulator of immune responses and an important participant in carcinogenesis and cancer progression. As a transcription factor, NF-κB targets genes that promote cell proliferation and survival. Constitutive or aberrant activation of NF-κB is encountered in many types of cancer, including CTCL.Recently, while analyzing gene-expression profiles of a variety of small molecule compounds that target NF-κB, we discovered the tetracycline family of antibiotics, including doxycycline, to be potent inhibitors of the NF-κB pathway. Doxycycline is well-tolerated, safe, and inexpensive; and is commonly used as an antibiotic and anti-inflammatory for the treatment a multitude of medical conditions.In our current study, we show that doxycycline induces apoptosis in a dose dependent manner in multiple different cell lines from patients with the two most common subtypes of CTCL, Mycosis Fungoides (MF) and Sézary Syndrome (SS). Similar results were found using primary CD4+ T cells from a patient with SS. Doxycycline inhibits TNF induced NF-κB activation and reduces expression of NF-κB dependent anti-apoptotic proteins, such as BCL2α. Furthermore, we have identified that doxycycline induces apoptosis through reactive oxygen species.
authors.affiliation: Rochester General Hospital Research Institute, Center for Cancer and Blood Disorders, Rochester, NY, USA.
authors.forename: Carolina V
authors.initials: CV
authors.lastname: Alexander-Savino
authors.affiliation: Rochester General Hospital Research Institute, Center for Cancer and Blood Disorders, Rochester, NY, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Hayden
authors.affiliation: Division of Allergy, Immunology and Rheumatology, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Richardson
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Rochester General Hospital Research Institute, Center for Cancer and Blood Disorders, Rochester, NY, USA.|Rochester Skin Lymphoma Center, Fairport, NY, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Poligone
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology*; D005260:Female; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012751:Sezary Syndrome / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8; D004318:Doxycycline
keywords: apoptosis; doxycycline; drug repurposing; non-Hodgkin’s lymphoma; signal transduction