NF-kappaB

NF-ƒÈB review

Archivum Immunologiae et Therapiae Experimentalis

December 2016, Volume 64, Issue 6, pp 463–483

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FromF Transcription Factor NF-ƒÈB: An Update on Intervention Strategies@Archivum Immunologiae et Therapiae Experimentalis@

Since NF-kappaB promotes angiogenesis and is involved in cancer progression, it acts as a major target for the therapeutic purposes. Various pharmacological substances like thalidomide, celecoxib, gemcitabine, cisplatin, doxorubicin, genistein, bortezomib, sulfasalazine and others either alone or in combination with radiotherapy or other pharmacological agents have already entered clinical studies and show promising results to treat various types of cancer@(Hada and Mizutari 2004c..)

 

The nuclear factor (NF) - ƒÈB family of transcription factors are ubiquitous and pleiotropic molecules that regulate the expression of more than 150 genes involved in a broad range of processes including inflammation, immunity, cell proliferation, differentiation, and survival.  Inducible NF-ƒÈB activation depends on degradation of the inhibitor of NF-ƒÈB proteins (IƒÈBs), which retain inactive NF-ƒÈB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-ƒÈB activation converge on the IƒÈB kinase (IKK) complex, and is essential for signal transduction to NF-ƒÈB. NF-ƒÈB can enter the nucleus. In this process histone deacetylase inhibitor valproic acid may play essential role. The five members of the mammalian NF-ƒÈB family, p65 (RelA), RelB, c-Rel, p50/p105 (NF-ƒÈB1), and p52/p100 (NF-ƒÈB2), exist in unstimulated cells as homo- or heterodimers bound to IƒÈB family proteins. NF-ƒÈB proteins are characterized by the presence of a conserved 300-amino acid Rel homology domain (RHD) that is located toward the N terminus of the protein and is responsible for dimerization, interaction with IƒÈBs, and binding to DNA. The chronic activation or dysregulation of NF-ƒÈB signaling is the central cause of pathogenesis in many disease conditions and, therefore, NF-ƒÈB is a major focus of therapeutic intervention. Because of this, understanding the relationship between NF-ƒÈB and the induction of various downstream signaling molecules is imperative. @

 

Treatments

‡@  Thalidomide{Celecoxib

‡A  Cytotoxic Drugs

‡B  Solafenib or Valproic Acid

Treatment targeting NF-kappa B is performed by combining the above three kinds of drugs.

 

NF-ƒÈ and cancers

Various types of solid tumors including breasts, ovarian, colon, thyroid, bladder, pancreatic and prostate carcinomas as well as melanomas are characterized by persistent activation of NF-ƒÈB transcription factors.

Breast cancer

Constitutive activation of NF-ƒÈB: converts breast cancer cells to hormone-independent growth, aggressive and metastatic tumor

NF-ƒÈB is activated by TNF-alpha and EGF, especially in estrogen receptor negative breast cancer cells

Ovarian cancer

NF-ƒÈB  acts as a biphasic regulator: tumor suppressor, inductor of apoptosis and oncogene

Thalidomide and celecoxib are potent synergistic drugs with cytotoxic drugs.

NF-ƒÈB acts as a key regulator for developing resistance to platinum-based chemotherapy and thus attributes to the aggressive recurrent ovarian cancer.

Pancreatic cancer

Rel A constitutive activated

For the control of the tumor microenvironment of pancreatic cancer, it is recommended that a combination of thalidomide and celecoxib and a simultaneous administration of cytotoxic drug.

Lung cancer

Activated  NF-ƒÈB

Factors associated with angiogenesis like VEGF, TNF-a, IL-8, IL-6, MCP-1, and matrix metalloproteinases are also activated by NF-ƒÈB in lung tumor cells, therefore it is important to use thalidomide an celecoxib to lung cancer chemotherapy.