Kamalakannan Palanichamy

A newly synthetic chromium complex - chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance

Low‐molecular‐weight organic chromium complexes such as chromium picolinate are often used as dietary supplements to improve insulin sensitivity and to correct dyslipidemia. However, toxicity associated with such chromium compounds has compromised their therapeutic value. The aim of this study was to evaluate the impact of a newly synthesized complex of chromium with phenylalanine, Cr(pa)3 on insulin‐signaling and glucose tolerance. Cr(pa)3 was synthesized by chelating chromium(III) with d‐phenylalanine ligand in aqueous solution. In mouse 3T3‐adipocytes, Cr(pa)3 augmented insulin‐stimulated glucose‐uptake as assessed by a radioactive‐glucose uptake assay. At the molecular level, Cr(pa)3 enhanced insulin‐stimulated phosphorylation of Akt in a time‐ and concentration‐dependent manner without altering the phosphorylation of insulin receptor. Oral treatment with Cr(pa)3 (150 μg/kg/d, for six weeks) in ob/ob(+/+) obese mice significantly alleviated glucose tolerance compared with untreated obese mice. Unlike chromium picolinate, Cr(pa)3 does not cleave DNA under physiological reducing conditions. Collectively, these data suggest that Cr(pa)3 may represent a novel, less‐toxic chromium supplement with potential therapeutic value to improve insulin sensitivity and glycemic control in type II diabetes.

Overcoming Therapeutic Resistance in Malignant Gliomas: Current Practices and Future Directions

Malignant gliomas remain among the most treatment-refractory tumors. Traditional upfront treatment regimens have incorporated nitrosurea-based chemotherapy. This strategy has evolved to include temozolomide-based approaches. Promising Phase I/II data with TMZ in the recurrent setting prompted a Phase III EORTC study of TMZ in combination with RT for patients with newly diagnosed GBM. The landmark EORTC 26981-22981/NCIC CE3 study demonstrated a significant improvement in not only median survival, but also in terms of 2-year survival. Given that over one-quarter of the patients enrolled on the TMZ + RT arm survived beyond 2-years, there appears to be a finite percentage of patients who derive long-term benefit from this treatment regimen. Given that the EORTC-based regimen represents an incremental improvement in the standard of care, rather than a truly curative solution for most patients, further efforts must be expended to identify novel therapeutic approaches. To this end, targeted therapies have emerged as an attractive option. Accumulating evidence suggests that certain molecular pathways are selectively upregulated in tumor vs. normal cells. Some of these pathways have been shown to be instrumental in proliferation, migration, invasion, angiogenesis, and/or survival in preclinical models. These would appear to represent ideal therapeutic targets, as their antagonism may lead to an improvement in the therapeutic ratio of radiation. Emerging data from clinical studies on first generation targeted therapies appear to demonstrate benefit for select patients. Further molecular/genetic profiling must be undertaken to identify exactly which patients benefit.

Antioxidant properties of argpyrimidine

Argpyrimidine, the product of non-enzymatic protein glycation by methylglyoxal, has been implicated in the pathophysiology of diabetes mellitus and neurodegenerative diseases. Chemically, argpyrimidine is a substituted pyrimidinol with structural features common to known antioxidants. The objective of this study was to investigate the antioxidant properties of argpyrimidine. Argpyrimidine was synthesized by mixing L-arginine with 3-acetoxypentane-2,4-dione under acidic conditions and purified by chromatography. Argpyrimidine inhibited lipid peroxidation of rat brain homogenates catalyzed by hydroxyl radicals, metal ions, and autooxidation in a concentration- and time-dependent manner. In addition, argpyrimidine scavenged superoxide anion, 1,1-diphenyl 2-picryl-hydrazyl-stable free radical, intracellular-hydrogen peroxide, and inhibited free-radical-mediated nicking of plasmid-DNA. Taken together, our data suggest that argpyrimidine has antioxidant properties and may therefore have biological relevance in pathophysiologies associated with diabetes mellitus and neurodegenerative diseases.

CT322, a VEGFR-2 antagonist, demonstrates anti-glioma efficacy in orthotopic brain tumor model as a single agent or in combination with temozolomide and radiation therapy.

Glioblastomas are among the most aggressive human cancers, and prognosis remains poor despite presently available therapies. Angiogenesis is a hallmark of glioblastoma, and the resultant vascularity is associated with poor prognosis. The proteins that mediate angiogenesis, including vascular endothelial growth factor (VEGF) signaling proteins, have emerged as attractive targets for therapeutic development. Since VEGF receptor-2 (VEGFR-2) is thought to be the primary receptor mediating angiogenesis, direct inhibition of this receptor may produce an ideal therapeutic effect. In this context, we tested the therapeutic effect of CT322, a selective inhibitor of VEGFR-2. Using an intracranial murine xenograft model (U87-EGFRvIII-luciferase), we demonstrate that CT322 inhibited glioblastoma growth in vivo and prolonged survival. Of note, the anti-neoplastic effect of CT322 is augmented by the incorporation of temozolomide or temozolomide with radiation therapy. Immunohistochemical analysis of CT322 treated tumors revealed decreased CD31 staining, suggesting that the tumoricidal effect is mediated by inhibition of angiogenesis. These pre-clinical results provide the foundation to further understand long term response and tumor escape mechanisms to anti-angiogenic treatments on EGFR over-expressing glioblastomas.

Impact of molecular profiling on clinical trial design for glioblastoma

This review highlights the ways in which molecular and genetic profiling of malignant gliomas has led to intelligent clinical trial design. The review also highlights known resistance mechanisms to conventional therapies in malignant gliomas and potential strategies to overcome these mechanisms with the use of targeted therapy.