Metformin Has Positive Therapeutic Effects in Colon Cancer and Lung Cancer.

BACKGROUND: Metformin (MF), a diabetic drug, has antineoplastic activity as adjuvant therapy for breast cancer and prostate cancer. MF is thought to work via inhibition of mammalian target of rapamycin and activation of p53 and liver kinase B1 via adenosine 5'-monophosphate-activated protein kinase. We investigated survival, recurrences and metastasis in patients with type 2 diabetes mellitus (DM2) along with colorectal cancer (CC) or lung cancer (LC) taking MF using the electronic medical record in Memphis Veterans Affairs Medical Center (colon, n = 202; lung, n = 180). MATERIALS AND METHODS: Patients with CC or LC and DM2 on MF were compared to controls taking any medication except MF. Recurrences, metastases, secondary cancers, survival and carcinoembryonic antigen levels were compared using t test and chi-squared test. Inclusion criteria were based on MF use, CC or LC diagnosis and DM2. RESULTS: For CC, the MF group noted fewer deaths (48% versus 76%, P < 0.001), recurrences (4% versus 19%, P = 0.002), metastases (23% versus 46%, P = 0.001), better 5-year survival rates (57% versus 37%, P = 0.004), overall survival years (5.7 versus 4.1, P = 0.007) and greater carcinoembryonic antigen decrease (72% versus 47%, P = 0.015). MF was associated with improved 5-year survival rates (29% versus 15%, P = 0.023) and overall survival years (3.4 versus 1.8, P < 0.001) in LC. CONCLUSIONS: Our study shows that MF therapy is associated with significantly better prognosis in patients with CC and improved survival in LC. Patients with CC on MF had fewer recurrences and metastases. Differences in metabolic pathways between CC and LC likely account for the differences in the effect of MF.

H2O2 activation of HSP25/27 protects desmin from calpain proteolysis in rat ventricular myocytes.

Ischemia-reperfusion-induced Ca(2+) overload results in activation of calpain-1 in the heart. Calpain-dependent proteolysis contributes to myocardial dysfunction and cell death. Previously, preischemic treatment with low doses of H(2)O(2) was shown to improve postischemic function and reduce myocardial infarct size. Our aim was to determine the mechanism by which H(2)O(2) protects the heart. We hypothesized that H(2)O(2) causes the activation of p38 MAPK which initiates translocation of heat shock protein 25/27 (HSP25/27) to the myofilament Z disk. We further hypothesized that HSP25/27 shields structural proteins, particularly desmin, from calpain-induced proteolysis. To address this hypothesis, we first determined that an ischemia-reperfusion-induced decrease in desmin content could be blocked by H(2)O(2) pretreatment of hearts from rats. We next determined that ventricular myocytes that underwent Ca(2+) overload also demonstrated a calpain-dependent disruption of desmin that could be reduced by H(2)O(2)/p38 MAPK activation. Furthermore, myocytes acutely treated with H(2)O(2) exhibited a decrease in cleavage of desmin upon exposure to exogenous calpain-1 compared with myocytes not pretreated with H(2)O(2). The H(2)O(2)-induced attenuation of desmin degradation by calpain-1 was blocked by inhibition of p38 MAPK. In a final series of experiments, we demonstrated that cardiac myofilaments exposed to recombinant phosphorylated HSP27, but not nonphosphorylated HSP27, had a significant reduction in the calpain-induced degradation of desmin compared with non-HSP27-treated myofilaments. These findings are consistent with the hypothesis that H(2)O(2)-induced activation of p38 MAPK and subsequent HSP25/27 translocation attenuates desmin degradation brought about by calpain-1 activation in ischemia-reperfused hearts.