Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rituximab (chimeric anti-CD20 monoclonal antibody) is currently being used, alone or in combination with chemotherapy, in the treatment of B-non-Hodgkin's lymphoma (B-NHL). We have reported that rituximab treatment of B-NHL cell lines sensitizes the drug-resistant tumor cells to apoptosis by various chemotherapeutic drugs and chemosensitization was, in large part, owing to the selective inhibition of the anti-apoptotic Bcl-(XL) gene product. The constitutive activation of the Akt pathway in B-NHL results in overexpression and functional activation of Bcl-(xL). Hence, we hypothesized that rituximab-induced inhibition of Bcl-(xL) expression and chemosensitization may result, in part, from its inhibitory activity of the Akt pathway. This hypothesis was tested using the drug-resistant Ramos and Daudi B-NHL cell lines. Time kinetic analysis revealed that treatment with rituximab inhibited phosphorylation of Akt, but not unphosphorylated Akt, and the inhibition was first detected at 6 h post-rituximab treatment. Similar time kinetics revealed rituximab-induced inhibition of p-PDK1, p-Bad, p-IKKalpha/beta and p-Ikappabetaalpha and no inhibition of unphosphorylated proteins. In addition, rituximab treatment resulted in significant increase of Bcl-(xL)-Bad heterodimeric complexes as compared to untreated cells. The role of the Akt pathway in the regulation of resistance was corroborated by the use of the Akt inhibitor, LY294002, and by transfection with siRNA Akt. Treatment of tumor cells with LY294002 or with Akt siRNA, but not control siRNA, resulted in inhibition of Bcl-(xL) expression and sensitization to drug-induced apoptosis. Although rituximab did not inhibit the Akt pathway nor sensitized the rituximab-resistant Ramos RR1 clone, treatment with LY294002 or Akt siRNA sensitized the clone to drug-induced apoptosis. The present findings demonstrate for the first time that rituximab inhibits the constitutively activated Akt pathway in B-NHL cell lines, and this inhibition contributes to sensitization of drug-resistant cells to apoptosis by chemotherapeutic drugs. The findings also identify the Akt pathway as target for therapeutic intervention in the reversal of rituximab and drug-resistant B-NHL.
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PMID:Rituximab inhibits the constitutively activated PI3K-Akt pathway in B-NHL cell lines: involvement in chemosensitization to drug-induced apoptosis. 2734 1

Dichloroacetate (DCA) is a promising safe anticancer drug that cured a patient with chemoresistant non-Hodgkin's lymphoma and treated lactic acidosis effectively. The well-known mechanism of DCA action is through stimulating Krebs cycle (stimulating pyruvate dehydrogenase via inhibiting pyruvate dehydrogenase kinase). This prevents lactate formation (Warburg effect) depriving cancer cells of lactate-based benefits e.g. angiogenesis, chemoresistance and radioresistance. Here, we introduce novel evidence-based hypotheses to explain DCA-induced anticancer effects. On pharmacological and biochemical bases, we hypothesize that DCA is a structural antagonist of acetate competing with it for target enzymes and biological reactions. We hypothesize that DCA exerts its anticancer effects via depriving cancer of acetate benefits. We hypothesize also that acetate is an antidote of DCA capable of treating DCA toxicity. Many reports support our hypotheses. Acetate is vital for cancer cells (tumors depend on acetate) and DCA is structurally similar to acetate. DCA exerts opposite effects to acetate. Acetate caused a decrease in serum potassium, phosphorus and glucose, and an increase in serum lactate, citrate, free fatty acids and ketone bodies (serum acetoacetate and beta-hydroxybutyrate levels). Acetate decreased the proportion of active (dephosphorylated) pyruvate dehydrogenase in perfused rat heart. DCA produced quite opposite effects. Intravenous infusion of acetate produced metabolic alkalemia while DCA caused minimal effects on acid-base status. Acetate is important for cancer cells metabolism and survival as elevated acetate can drive resistance to targeted cancer treatments. Acetate is required for epidermal growth factor receptor vIII mutation in lethal brain tumors. Experimentally, DCA inhibited acetate oxidation in hearts of normal rats and reversed inhibitory effects of acetate on the oxidation of glucose. During presence of DCA with no glucose in heart perfusions with [1-14C]acetate, DCA decreased the specific radioactivity of acetyl CoA and its product citrate. This proves our hypotheses that DCA is an antimetabolite that antagonizes acetate for vital reactions in cancer cells. Acetate may be used as an antidote to combat DCA toxicity.
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PMID:Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis. 3059 13