NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B （NF-κB）, a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-κB activation in inflammatory bowel diseases （IBDs） increases risk of colorectal cancer （CRC） in the patients with the number of years of active disease. NF-κB activation might induce cellular transformation, mediate cellular proliferation, prevent the elimination of pre-neoplastic and fully malignant cells by up-regulating the anti-apoptosis proteins. Furthermore, NF-κB may contribute to the progression of CRC by regulating the expression of diverse target genes that are involved in cell proliferation （Cyclin D1）, angiogenesis （VEGF, IL-8, COX2）, and metastasis （MMP9）. These findings implicate NF-κB inhibition as an important therapeutic target in CRC. However, due to lack of knowledge about the specific roles of different NF-r,B subunits in different stage of carcinogenesis, and compounds to block specific subunits of NF-κB family, it will be a long time before the coming of targeting NF-κB in CRC therapy.

Novel natural product therapeutics targeting both inflammation and cancer

Inflammation is recently recognized as one of the hallmarks of human cancer. Chronic inflammatory response plays a critical role in cancer development, progression, metastasis, and resistance to chemotherapy. Conversely, the oncogenic aberrations also generate an inflammatory microenvironment, enabling the development and progression of cancer. The molecular mechanisms of action that are responsible for inflammatory cancer and cancer-associated inflammation are not fully understood due to the complex crosstalk between oncogenic and pro-inflammatory genes. However, molecular mediators that regulate both inflammation and cancer, such as NF-κB and STAT have been considered as promising targets for preventing and treating these diseases. Recent works have further demonstrated an important role of oncogenes(e.g., NFAT1, MDM2) and tumor suppressor genes(e.g., p53) in cancer-related inflammation. Natural products that target these molecular mediators have shown anticancer and anti-inflammatory activities in preclinical and clinical studies. Sesquiterpenoids(STs), a class of novel plant-derived secondary metabolites have attracted great interest in recent years because of their diversity in chemical structures and pharmacological activities. At present, we and other investigators have found that dimeric sesquiterpenoids(DSTs) may exert enhanced activity and binding affinity to molecular targets due to the increased number of alkylating centers and improved conformational flexibility and lipophilicity. Here, we focus our discussion on the activities and mechanisms of action of STs and DSTs in treating inflammation and cancer as well as their structure-activity relationships.

Cancer induction pathways and HF-EMF irradiation

The response of cells to different types of electromagnetic fields can be induced by low-level (athermal) high frequency (HF) electromagnetic field (EMF) exposure associated with mobile phone technologies. There are many examples of biological effects involving the epigenome. EMF could trigger protein activation mediated by ligands, such as Ca2+, that alter the conformation of binding proteins, especially the NADPH plasmic membrane oxidase, so inducing increased formation of reactive oxygen species (ROS) that may alter proteomic functions. Classical antiapoptotic and procarcinogenic signaling mechanisms that are commonly found activated in human malignancies and in inflammation mainly involve the transcription factor NF-κB. The microenvironment that exists during chronic inflammation can contribute to cancer progression. The data support the proposition that long term HF-EMF exposure caused by improper use of cell phones may potentially cause cancer.