The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, MEK1, DUSP5, PP2A, PIK3CA, PIK3R1, PIK3R4, PIK3R5, IRS4, AKT, NFKB1, MTOR, PTEN, TSC1, and TSC2 may also be activated/inactivated by mutations or epigenetic silencing. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of these cascades can contribute to: resistance to other pathway inhibitors, chemotherapeutic drug resistance, premature aging as well as other diseases. This review will first describe these pathways and discuss how genetic mutations and epigenetic alterations can result in resistance to various inhibitors.

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic in ammation. The aim of our study was to assess whether plasma markers of in ammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 6 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 6 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFa) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-I were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if posttreadmill concentrations were signi cantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001).These results con rm that white blood cell activation is characteristic of systemic atherosclerosis and that these in ammation markers increase in conditions of hemodynamic stress.

Previous studies have detected high levels of matrix metalloproteinases (MMPs) in metastatic prostate cancer. In this study, we recruited 40 patients with prostate cancer (PCa): 20 presented organ-confined carcinoma and 20 had metastatic cancer. We also recruited 40 subjects for control groups, 20 with benign prostate hyperplasia (BPH) and 20 healthy males with similar characteristics. All of the patients were monitored at the beginning (time 0) and after 90 days. We analyzed the plasma concentrations of MMP-2, MMP-9, MMP-13, TIMP-1 and the enzyme activity of MMP-2 and MMP-9,using specific ELISA tests. The plasma concentrations of MMP-2, MMP-9 and MMP-13 were higher in PCa patients with metastasis than in the other groups, and in these patients decreased markedly after therapy began. For MMP-2 and MMP-9, greater differences were observed in enzyme activity than in plasma concentrations. TIMP-1 was reduced in PCa patients with metastasis, even if the intergroup differences were not statistically significant. Our results suggest that the plasma concentration and activity of MMPs, in association with PSA determination, could play a role in diagnosis, monitoring therapy and evaluating malignant progression in PCa.