b29ed72e3469310cf01b6362d16ec853 pmc_28208677.pdf 04f6d497a53af8502babaebc0b5c1ad0c4b3b8b9 pmc_28208677.pdf c11ea6e53551d0517ae6a20e6233b1ba325bb7da90fa7e995e1bbe8acd7c1397 pmc_28208677.pdf Title: Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice Subject: Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 2.0 and TMZ: 38.7 2.7, n = 6) and controls (22.5 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response. Keywords: glioma; preclinical brain tumour; GBM therapeutic target; CK2 inhibitors; CX-4945; metronomic therapy; immune system Author: Laura Ferrer-Font, Lucia Villamañan, Nuria Arias-Ramos, Jordi Vilardell, Maria Plana, Maria Ruzzene, Lorenzo A. Pinna, Emilio Itarte, Carles Arús and Ana Paula Candiota Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.15 CreationDate: Fri Feb 17 05:12:22 2017 CET ModDate: Fri Feb 17 05:12:22 2017 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2491551 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ZZNLAF+URWPalladioL-Ital Type 1 Custom yes yes no 139 0 CUELLZ+URWPalladioL-Bold Type 1 Custom yes yes no 140 0 ENLEMO+VnURWPalladioL-Bold Type 1 Custom yes yes no 141 0 VNWBCY+URWPalladioL-Roma Type 1 Custom yes yes no 142 0 MAYSLG+VnURWPalladioL Type 1 Custom yes yes no 143 0 VYVZGZ+CMSY10 Type 1 Builtin yes yes no 144 0 VWRBXB+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 148 0 JDWIZJ+EURM10 Type 1 Builtin yes yes no 191 0 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ぎはの〭きづぴひはのはねどっ〠ぃはねぢどのづつ〠ぃじ〭〴〹〴〵〠ちのつ〠ごきず〠がはのでどぴふつどのちぬ〠ぉの〠ざどぶは〠こぴふつどづび〠 Item: Title: きづぴひはのはねどっ〠ぃじ〭〴〹〴〵〠ちのつ〯はひ〠ごきず〠がはのでどぴふつどのちぬ〠ぉの〠ざどぶは〠こぴふつどづび〠ちのつ〠ぐはびびどぢぬづ〠ぉねばぬどっちぴどはの〠はて〠ぴとづ〠ぉねねふのづ〠こべびぴづね〠 Item: Title: きちぴづひどちぬび〠ちのつ〠きづぴとはつび〠 Children: Item: Title: ぇが〲〶〱〠ぃづぬぬび〠 Item: Title: ぃづぬぬ〠ざどちぢどぬどぴべ〠ぁびびちべ〠 Item: Title: ぁのぴどぢはつどづび〠 Item: Title: ごちひでづぴ〠ぅぶちぬふちぴどはの〠どの〠ぇが〲〶〱〠ぃふぬぴふひづつ〠ぃづぬぬび〠ぷどぴと〠ぃじ〭〴〹〴〵〠ごひづちぴねづのぴ〠 Item: Title: ぁのどねちぬ〠きはつづぬ〠てはひ〠ぉの〠ざどぶは〠こぴふつどづび〠 Item: Title: ぃじ〭〴〹〴〵〠ちのつ〠ごきず〠ごはぬづひちぢどぬどぴべ〠ぁびびちべ〠 Item: Title: さびづ〠はて〠どぃか〲〠どの〠ごふねはふひ〭あづちひどので〠ぁのどねちぬび〠 Children: Item: Title: ぐひづぬどねどのちひべ〠こぴふつどづび〠はて〠ごちひでづぴ〠ざちぬどつちぴどはの〠 Item: Title: がはのでどぴふつどのちぬ〠こぴふつどづび〠ぷどぴと〠どぃか〲〠〨ちぬはのづ〠はひ〠どの〠っはねぢどのちぴどはの〩〠 Item: Title: ぃか〲〠ぁっぴどぶどぴべ〠ぁびびちべ〠 Item: Title: きげぉ〠ぁっぱふどびどぴどはの〠 Item: Title: ごどびびふづ〠えはねはでづのどぺちぴどはの〠ちのつ〠ぐひはぴづどの〠ぅへぴひちっぴどはの〯しづびぴづひの〠あぬはぴ〠ぁのちぬべびどび〠 Item: Title: こぴちぴどびぴどっちぬ〠ぁのちぬべびどび〠 Item: Title: ぃはのっぬふびどはのび〠 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: VYVZGZ+CMSY10 FontSubset: true FirstChar: 2 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18 Annotations: Annotation: Subtype: Link Rect: 478, 727, 516, 738 Annotation: Subtype: Link Rect: 100, 715, 136, 725 Annotation: Subtype: Link Rect: 292, 689, 329, 699 Annotation: Subtype: Link Rect: 336, 689, 372, 699 Annotation: Subtype: Link Rect: 414, 663, 451, 674 Annotation: Subtype: Link Rect: 458, 663, 494, 674 Annotation: Subtype: Link Rect: 478, 637, 516, 648 Annotation: Subtype: Link Rect: 100, 625, 136, 635 Annotation: Subtype: Link Rect: 342, 585, 380, 596 Annotation: Subtype: Link Rect: 386, 585, 422, 596 Annotation: Subtype: Link Rect: 408, 546, 445, 557 Annotation: Subtype: Link Rect: 451, 546, 487, 557 Annotation: Subtype: Link Rect: 261, 508, 298, 519 Annotation: Subtype: Link Rect: 304, 508, 340, 519 Annotation: Subtype: Link Rect: 100, 470, 137, 480 Annotation: Subtype: Link Rect: 143, 470, 179, 480 Annotation: Subtype: Link Rect: 333, 430, 370, 441 Annotation: Subtype: Link Rect: 377, 430, 413, 441 Annotation: Subtype: Link Rect: 100, 392, 137, 402 Annotation: Subtype: Link Rect: 143, 392, 179, 402 Annotation: Subtype: Link Rect: 212, 378, 331, 390 Annotation: Subtype: Link Rect: 302, 340, 339, 351 Annotation: Subtype: Link Rect: 346, 340, 382, 351 Annotation: Subtype: Link Rect: 222, 327, 360, 338 Annotation: Subtype: Link Rect: 437, 276, 474, 286 Annotation: Subtype: Link Rect: 480, 276, 516, 286 Annotation: Subtype: Link Rect: 75, 234, 165, 265 Annotation: Subtype: Link Rect: 233, 228, 423, 239 Checksum: 39c3e503 Type: CRC32 Checksum: b29ed72e3469310cf01b6362d16ec853 Type: MD5 Checksum: 04f6d497a53af8502babaebc0b5c1ad0c4b3b8b9 Type: SHA-1 Checksum: c11ea6e53551d0517ae6a20e6233b1ba325bb7da90fa7e995e1bbe8acd7c1397 Type: SHA-256