Investigation of the Anticancer Activity of the Temozolomide and Palomid 529 Combination in Glioblastoma Cells

Project no. 32879 · Status: Kapanmış · 2025

Summary

<p>Glioblastoma&nbsp;(GBM)&nbsp;is&nbsp;one&nbsp;of&nbsp;the&nbsp;most&nbsp;common&nbsp;and&nbsp;clinically&nbsp;aggressive&nbsp;primary&nbsp;malignant</p><p>brain&nbsp;tumors&nbsp;in&nbsp;the&nbsp;adult&nbsp;population.&nbsp;This&nbsp;tumor&nbsp;type&nbsp;is&nbsp;regarded&nbsp;as&nbsp;a&nbsp;highly&nbsp;challenging</p><p>malignancy&nbsp;to&nbsp;treat&nbsp;due&nbsp;to&nbsp;its&nbsp;marked&nbsp;proliferative&nbsp;capacity,&nbsp;invasive/infiltrative&nbsp;spread&nbsp;into</p><p>the&nbsp;surrounding&nbsp;brain&nbsp;parenchyma,&nbsp;and&nbsp;association&nbsp;with&nbsp;poor&nbsp;prognosis.&nbsp;Although&nbsp;the&nbsp;current</p><p>standard&nbsp;multimodal&nbsp;treatment&nbsp;approach&nbsp;consists&nbsp;of&nbsp;surgical&nbsp;resection,&nbsp;radiotherapy,&nbsp;and</p><p>temozolomide&nbsp;(TMZ)-based&nbsp;chemotherapy,&nbsp;the&nbsp;development&nbsp;of&nbsp;therapeutic&nbsp;resistance&nbsp;in</p><p>tumor&nbsp;cells&nbsp;remains&nbsp;one&nbsp;of&nbsp;the&nbsp;major&nbsp;obstacles&nbsp;in&nbsp;the&nbsp;clinical&nbsp;management&nbsp;of&nbsp;glioblastoma.</p><p>Activation&nbsp;of&nbsp;the&nbsp;PI3K/Akt/mTOR&nbsp;signaling&nbsp;pathway&nbsp;has&nbsp;been&nbsp;reported&nbsp;to&nbsp;play&nbsp;a&nbsp;particularly</p><p>important&nbsp;role&nbsp;in&nbsp;these&nbsp;resistance&nbsp;mechanisms.</p><p></p><p>In&nbsp;this&nbsp;study,&nbsp;the&nbsp;effects&nbsp;of&nbsp;Palomid&nbsp;529&nbsp;(P529),&nbsp;a&nbsp;dual&nbsp;TORC1/2&nbsp;inhibitor&nbsp;capable&nbsp;of&nbsp;crossing</p><p>the&nbsp;blood-brain&nbsp;barrier,&nbsp;were&nbsp;evaluated&nbsp;in&nbsp;the&nbsp;glioblastoma&nbsp;T98G&nbsp;cell&nbsp;line&nbsp;both&nbsp;as&nbsp;a&nbsp;single</p><p>agent&nbsp;and&nbsp;in&nbsp;combination&nbsp;with&nbsp;temozolomide.&nbsp;Cell&nbsp;viability&nbsp;and&nbsp;cytotoxicity&nbsp;levels&nbsp;were</p><p>determined&nbsp;using&nbsp;the&nbsp;WST-8&nbsp;assay,&nbsp;while&nbsp;the&nbsp;drug&nbsp;interaction&nbsp;between&nbsp;Palomid&nbsp;529&nbsp;and</p><p>temozolomide&nbsp;was&nbsp;assessed&nbsp;through&nbsp;isobologram&nbsp;analysis&nbsp;and&nbsp;combination&nbsp;index&nbsp;(CI)</p><p>calculations.&nbsp;In&nbsp;addition,&nbsp;treatment-induced&nbsp;alterations&nbsp;in&nbsp;gene&nbsp;expression&nbsp;were&nbsp;analyzed</p><p>using&nbsp;qRT-PCR.</p><p></p><p>The&nbsp;results&nbsp;demonstrated&nbsp;that&nbsp;Palomid&nbsp;529&nbsp;exerted&nbsp;cytotoxic&nbsp;effects&nbsp;even&nbsp;at&nbsp;low</p><p>concentrations&nbsp;and&nbsp;enhanced&nbsp;the&nbsp;efficacy&nbsp;of&nbsp;temozolomide&nbsp;by&nbsp;reducing&nbsp;its&nbsp;ED50&nbsp;value</p><p>approximately&nbsp;twofold.&nbsp;The&nbsp;CI&nbsp;value&nbsp;of&nbsp;0.76&nbsp;was&nbsp;calculated&nbsp;for&nbsp;the&nbsp;combination&nbsp;treatment</p><p>indicated&nbsp;a&nbsp;moderate&nbsp;synergistic&nbsp;interaction&nbsp;between&nbsp;temozolomide&nbsp;and&nbsp;Palomid&nbsp;529.</p><p>Overall,&nbsp;these&nbsp;findings&nbsp;suggest&nbsp;that&nbsp;the&nbsp;TORC1/2&nbsp;inhibitor&nbsp;Palomid&nbsp;529&nbsp;may&nbsp;enhance&nbsp;the</p><p>anticancer&nbsp;efficacy&nbsp;of&nbsp;temozolomide&nbsp;and&nbsp;may&nbsp;represent&nbsp;a&nbsp;promising&nbsp;combination&nbsp;strategy&nbsp;for</p><p>overcoming&nbsp;resistance&nbsp;mechanisms&nbsp;associated&nbsp;with&nbsp;the&nbsp;PI3K/Akt/mTOR&nbsp;signaling&nbsp;pathway</p><p>in&nbsp;glioblastoma.</p>

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