SphK1 is overexpressed in a number of human cancers (Shida et al., 2008), raising the possibility that it is this upregulation and concomitant S1P production, at least in part, which constitutes the link in between pro-inflammation and pro-cancer environments. In any occasion, it can be now clear that S1P can promote carcinogenesis selleck product by a number of mechanisms such as enhancing tumor growth, angiogenesis, and metastasis. Believe it or not, SphK1 activity often correlates with higher tumor clinical grade, resistance to chemo- and radiotherapy, and poor patient prognosis (Pyne & Pyne, 2010). As disruption of S1P signaling has the potential to curtail processes critical to both cancer and inflammatory disease, it has deservedly been the subject of intense research interest. The significant morbidity and mortality associated with these pathologies in conjunction with the limitations of presently available therapies?which includes the high toxicity of quite a few anti-cancer drugs, the problem of drug resistance in tumor cells, and the deleterious side effects associated with common anti-inflammatory medications?only serve to underscore the urgency of this work. Recent efforts to identify and establish therapeutic uses for small molecule inhibitors of S1P signaling in cancer as well as various inflammatory and autoimmune diseases (Table 1) are highlighted below.
4.1. Cancer While cancer is more often than not referred to as a monolithic entity, the term encompasses a group of diseases that, beyond sharing the common feature of uncontrolled cell growth, are incredibly varied in presentation and etiology. This diversity presents a significant obstacle to the development of widely applicable cancer therapies. For example, a drug demonstrating efficacy against one form of the disease may have no effect or even be deleterious in other forms. Thus, the ubiquitous SphK1/S1P axis, as discussed above, is a very attractive therapeutic target for cancer. Treatment Clofarabine of head and neck cancer, in particular, is quite often limited by drug toxicity, resistance to chemotherapy and radiation, as well as the anatomical density of the region. Survival rates for these types of malignancy have not improved significantly over the past 20 years, indicating that new therapeutic options are desperately needed (Beckham et al., 2010). The results of various preclinical studies suggest that modulation of S1P signaling could prove a fruitful approach to this problem. For example, SphK1 overexpression is known to correlate with poor prognosis in patients with glioblastoma multiforme (GBM), the most common and lethal form of central nervous system malignancy (Van Brocklyn et al., 2005). Accordingly, a recent report demonstrated the efficacy of the potent SphK1 inhibitor (2R,3S,4E)-N-methyl-5-(4?-pentylphenyl)-2-aminopent-4-ene-1,3-diol, referred to as SK1-I, in cultured human GBM cells as well as in glioblastoma xenografts (Kapitonov et al., 2009).