Doxycycline is an NF-κB inhibitor that induces apoptotic cell death in malignant T-cells
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Carolina V. Alexander-Savino1, Matthew S. Hayden1, Christopher Richardson2, Jiyong Zhao3, Brian Poligone1,4
1Rochester General Hospital Research Institute, Center for Cancer and Blood Disorders, Rochester, NY, USA
2Division of Allergy, Immunology and Rheumatology, University of Rochester School of Medicine, Rochester, NY, USA
3Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, NY, USA
4Rochester Skin Lymphoma Center, Fairport, NY, USA
Brian Poligone, email: [email protected]
Keywords: non-Hodgkin’s lymphoma, signal transduction, apoptosis, drug repurposing, doxycycline
Received: February 26, 2016 Accepted: September 24, 2016 Published: October 06, 2016
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.
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