Agent For Treatment Of Gliomas Research Articles

EXTH-54. ENHANCED SENSITIVITY OF HUMAN GLIOMA CELLS FOR TEMOZOLOMIDE (TMZ) BY COMBINING THERAPY WITH HEAT SHOCK PROTEIN 90

Abstract BACKGROUND Heat-shock protein 90 (HSP90) is a molecular chaperone involved in the conformational maturation of many client proteins that regulate cell proliferation, survival, and apoptosis. Due to the limited solubility of natural Hsp90 inhibitors, synthetic inhibitors with a more potent impact are being developed. In this study we examined the biological activity of a potent synthetic small molecule Hsp90 inhibitor, SNX-5422 (PF-04929113)and assessed its ability of to inhibit the growth of glioma and to synergize with temozolomide. We also examined the ability of SNX-5422 to cross the blood brain barrier (BBB) and to achieve target inhibition in vivo. METHODS Using a combination of in vitro techniques, the effect of SNX-5422 on the biological impact and HSP90 client protein signaling were studied in glioma lines and patient-derived glioma stem like cells. Its efficacy as a single agent or in combination with TMZ was also assessed in vitro. To assess SNX-5422 ability to cross blood brain barrier, brain and plasma pharmacokinetics was performed in non-tumor bearing mice. RESULTS SNX-5422 exhibited potent growth inhibition in both glioma cells and GSCs with an IC50 range of 100-500nM, and inhibited pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6 following treatment in GSC262 and GSC811. This was accompanied by accumulation of apoptotic cells following SNX-5422 exposure. Combination studies with TMZ showed a synergestic impact on glioma cell proliferation. Pharmacokinetics studies showed a significant drug penetrance into the intact brain further supported by elevated levels of HSP70 (molecular maker for HSP90 inhibition) by IHC. CONCLUSIONS SNX-5422 is effective in downregulating Hsp90 client proteins required for glioma cell survival. In addition, SNX-5422 inhibits tumor growth by promoting apoptosis through modulation of several key signaling pathways and sensitizes glioma cells to TMZ. Given also that SNX-5422 crosses BBB, it warrants further investigation as a clinical agent for treatment of gliomas.

The effects of neurolipins and their synthetic analogues on normal and transformed glial cells

In this work, we studied the effects of endogenous and synthetic derivatives of polyunsaturated fatty acids (neurolipins) on the viability of cells of rat C6 glioma and human U251 glioma cells. We synthesized 46 analogues of endogenous substances, amides and esters of fatty acids, with different modifications of the carboxyl group. We studied the four following groups of substances: analogues of 2-arachidonoyl glycerol and N-arachidonoylethanolamine, N-acyl amino acids, and N-acyl dopamines. Among all substances studied, N-acyl dopamines, in particular N-arachidonoyl dopamine (AA-DA) and N-docosahexaenoyl dopamine (DHA-DA) had the highest activities at concentrations below 10 μM. Our studies on the mechanisms of toxicity of AA-DA and DHA-DA showed that suppression of viability did not involve intracellular cascades that include mitogen-activated kinases, protein kinases C and A, and calmodulin-dependent kinases. We showed that toxic effects are developed through the caspase-dependent pathway, which includes activation of caspases 3 and 9. Note that AA-DA and DHA-DA at the same concentrations did not suppress the viability of normal glial cells and neurons of rats, which suggests that this group of substances may be used as a basis for the development of pharmacological agents for treatment of gliomas.