Paclitaxel effects on the proteome of HL-60 promyelocytic leukemic cells: comparison to peloruside A.

Paclitaxel (Taxol®), a drug used to treat solid tumors of the breast, ovary and lung, stabilizes microtubules and arrests cells in G(2)/M of the cell cycle. Using two-dimensional differential in-gel electrophoresis (DIGE), we examined the proteomic response of a human HL-60 promyeloid leukemic cell line to paclitaxel. Our intention was to compare the effects of paclitaxel to those of a new-generation microtubule-stabilizing agent, peloruside A, investigated in an earlier study. In response to 100 nM paclitaxel treatment for 24 h, 21 identified proteins changed in abundance, with 13 increases and 8 decreases. In addition, 21 other unidentified proteins were also changed by treatment with paclitaxel. Using Western blotting, the transcription factor c-Myc was shown to be reduced in abundance by both drugs. Our results showed both differences and similarities at the single protein level between paclitaxel and peloruside A, although the same general classes of proteins: cytoskeletal, nucleic acid binding, stress, and apoptotic proteins, changed following exposure. The proteomic response to paclitaxel was more extensive than the response to an equipotent dose of peloruside A.

Dendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy.

Heparanase is a mammalian endoglycosidase that cleaves heparan sulfate (HS) polysaccharides and contributes to remodelling of the extracellular matrix and regulation of HS-binding protein bioavailabilities. Heparanase is upregulated in malignant cancers and inflammation, aiding cell migration and the release of signaling molecules. It is established as a highly druggable extracellular target for anticancer therapy, but current compounds have limitations, because of cost, production complexity, or off-target effects. Here, we report the synthesis of a novel, targeted library of single-entity glycomimetic clusters capped with simple sulfated saccharides. Several dendrimer HS glycomimetics display low nM IC50 potency for heparanase inhibition equivalent to comparator compounds in clinical development, and potently inhibit metastasis and growth of human myeloma tumor cells in a mouse xenograft model. Importantly, they lack anticoagulant activity and cytotoxicity, and also inhibit angiogenesis. They provide a new candidate class for anticancer and wider therapeutic applications, which could benefit from targeted heparanase inhibition.

Remote ischaemic preconditioning does not alter perioperative cytokine production in high-risk cardiac surgery.

RATIONALE: Remote ischaemic preconditioning (RIPC) is a novel cardioprotective strategy that uses brief intermittent limb ischaemia to protect the myocardium and other organs from perioperative ischaemic damage. The precise mechanism through which this protective effect occurs is unknown, but potentially could be related to changes in blood-borne mediators such as cytokines. OBJECTIVE: To determine whether RIPC alters inflammatory cytokine expression in a double-blind, randomised, controlled trial of patients undergoing high-risk cardiac surgery. METHODS AND RESULTS: Serum interleukin (IL)-6, IL-8, and IL-10 levels from 95 patients randomised to RIPC (n=47) or control treatment (n=48) were measured preoperatively, and 1, 2, 3, 6 and 12 h after cross-clamp removal. Systemic concentrations of all cytokines were increased from baseline following surgery, and, compared with simple procedures, complex surgeries were associated with significantly higher release of IL-6 (ratio of mean area under the curves 1.54 (95% CI 1.02 to 2.34), p=0.04) and IL-10 (1.97 (1.16 to 3.35), p=0.012). No significant difference in mean cytokine levels between the RIPC and control groups was detected at any time point, irrespective of the type of surgery undergone. CONCLUSIONS: High levels of IL-6, IL-8 and IL-10 are produced during high-risk cardiac surgery, and RIPC does not alter these elevated perioperative cytokine concentrations. Identification of factors that influence the ability to induce RIPC-mediated cardioprotection should be the priority of future research. TRIAL REGISTRATION: is in the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au; ACTRN12609000965202).