Journal
ONCOTARGET
Volume 7, Issue 46, Pages 75954-75967Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12488
Keywords
non-Hodgkin's lymphoma; signal transduction; apoptosis; drug repurposing; doxycycline
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Funding
- Rochester General Hospital Skin Disease Research Fund
- James P. Wilmot Cancer Fellowship
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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-lambda B, a regulator of immune responses and an important participant in carcinogenesis and cancer progression. As a transcription factor, NF-lambda B targets genes that promote cell proliferation and survival. Constitutive or aberrant activation of NF-lambda B 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-lambda B, we discovered the tetracycline family of antibiotics, including doxycycline, to be potent inhibitors of the NF-lambda B 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 Sezary Syndrome (SS). Similar results were found using primary CD4+ T cells from a patient with SS. Doxycycline inhibits TNF induced NF-lambda B activation and reduces expression of NF-lambda B dependent antiapoptotic proteins, such as BCL2 beta. Furthermore, we have identified that doxycycline induces apoptosis through reactive oxygen species.
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