Matches in SemOpenAlex for { <https://semopenalex.org/work/W2562926397> ?p ?o ?g. }
Showing items 1 to 88 of
88
with 100 items per page.
- W2562926397 abstract "Background In order to survive bladder cancer (BCa) cells deregulate key pathways - including the inhibition of apoptosis - while developing “oncogene addiction” to molecular chaperones such as Heat Shock Protein 90 (HSP90). While successful in vitro, monotherapies targeting such pathways have failed in clinical trials. We aim to show the superiority of combination therapy using proteostatic and targeted cytotoxic agents. We hypothesize that these combinations will synergize to increase cytotoxicity (CT) in BCa by amplifying the apoptosis via simultaneous activation of both intrinsic and extrinsic apoptotic pathways. Methods The proteostatic agents tested were the HSP90 inhibitor STA9090 (9090) and the proteasome inhibitor Marizomib (NPI). The cytotoxic agent used was a synthetic TRAIL ligand. These agents were tested in multiple ATCC BCa cell lines and the NCI patient tumor-derived BCa cell line UOBL 101 (UOBL). CT was determined via MTT assay. Mechanism of cytotoxic response was investigated using a series of immunoblots targeting the components of intrinsic and extrinsic apoptotic pathways and nuclear degradation proteins. All the assays were performed in triplicates for validation. Results 9090 (IC50 7.4-10 nM) was effective in all cell lines, as was NPI (IC50 10-20 nM). TRAIL caused 100% CT in UOBL (IC50 2.5 ng/mL, 95% CI [1.0, 7.0]) and a maximal 50% CT in T24, however the cytotoxicity of individual agents was not sustained. Combination effects of 9090 + TRAIL and NPI + TRAIL demonstrated an increase from 50% CT to 100% CT at the IC50 of both 9090 and NPI, and this effect was sustained over the course of the experiment. The increased cytotoxicity of combination therapy had corresponded to rapid cytoplasmic release of cytochrome c, additive increase in cleaved caspase 3 and caspase 8, with the corresponding increase in cleaved PARP and γ-H2ax. Conclusions Combination of a pro-apoptotic agent with a molecular chaperone or proteasome inhibitor holds promise in BCa therapyby affecting intracellular anti-apoptotic signaling and compromising efficient proteostasis in cancer cells lines, and should be investigated further. Citation Format: Raju Chelluri, Piyush K. Agarwal, Leonard M. Neckers, Armine K. Smith. Synergistic effect of targeted combination therapy in bladder cancer model using HSP90 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3796. doi:10.1158/1538-7445.AM2015-3796" @default.
- W2562926397 created "2017-01-06" @default.
- W2562926397 creator A5029783170 @default.
- W2562926397 creator A5079993679 @default.
- W2562926397 creator A5084627594 @default.
- W2562926397 creator A5091789689 @default.
- W2562926397 date "2015-08-01" @default.
- W2562926397 modified "2023-09-25" @default.
- W2562926397 title "Abstract 3796: Synergistic effect of targeted combination therapy in bladder cancer model using HSP90 inhibitors" @default.
- W2562926397 doi "https://doi.org/10.1158/1538-7445.am2015-3796" @default.
- W2562926397 hasPublicationYear "2015" @default.
- W2562926397 type Work @default.
- W2562926397 sameAs 2562926397 @default.
- W2562926397 citedByCount "0" @default.
- W2562926397 crossrefType "proceedings-article" @default.
- W2562926397 hasAuthorship W2562926397A5029783170 @default.
- W2562926397 hasAuthorship W2562926397A5079993679 @default.
- W2562926397 hasAuthorship W2562926397A5084627594 @default.
- W2562926397 hasAuthorship W2562926397A5091789689 @default.
- W2562926397 hasConcept C104317684 @default.
- W2562926397 hasConcept C109316439 @default.
- W2562926397 hasConcept C121608353 @default.
- W2562926397 hasConcept C126322002 @default.
- W2562926397 hasConcept C154317977 @default.
- W2562926397 hasConcept C185592680 @default.
- W2562926397 hasConcept C190283241 @default.
- W2562926397 hasConcept C202751555 @default.
- W2562926397 hasConcept C205260736 @default.
- W2562926397 hasConcept C2775932338 @default.
- W2562926397 hasConcept C2776999253 @default.
- W2562926397 hasConcept C2777560012 @default.
- W2562926397 hasConcept C2777752497 @default.
- W2562926397 hasConcept C2778367456 @default.
- W2562926397 hasConcept C2780783641 @default.
- W2562926397 hasConcept C2781018059 @default.
- W2562926397 hasConcept C29537977 @default.
- W2562926397 hasConcept C502942594 @default.
- W2562926397 hasConcept C55493867 @default.
- W2562926397 hasConcept C71924100 @default.
- W2562926397 hasConcept C98274493 @default.
- W2562926397 hasConceptScore W2562926397C104317684 @default.
- W2562926397 hasConceptScore W2562926397C109316439 @default.
- W2562926397 hasConceptScore W2562926397C121608353 @default.
- W2562926397 hasConceptScore W2562926397C126322002 @default.
- W2562926397 hasConceptScore W2562926397C154317977 @default.
- W2562926397 hasConceptScore W2562926397C185592680 @default.
- W2562926397 hasConceptScore W2562926397C190283241 @default.
- W2562926397 hasConceptScore W2562926397C202751555 @default.
- W2562926397 hasConceptScore W2562926397C205260736 @default.
- W2562926397 hasConceptScore W2562926397C2775932338 @default.
- W2562926397 hasConceptScore W2562926397C2776999253 @default.
- W2562926397 hasConceptScore W2562926397C2777560012 @default.
- W2562926397 hasConceptScore W2562926397C2777752497 @default.
- W2562926397 hasConceptScore W2562926397C2778367456 @default.
- W2562926397 hasConceptScore W2562926397C2780783641 @default.
- W2562926397 hasConceptScore W2562926397C2781018059 @default.
- W2562926397 hasConceptScore W2562926397C29537977 @default.
- W2562926397 hasConceptScore W2562926397C502942594 @default.
- W2562926397 hasConceptScore W2562926397C55493867 @default.
- W2562926397 hasConceptScore W2562926397C71924100 @default.
- W2562926397 hasConceptScore W2562926397C98274493 @default.
- W2562926397 hasLocation W25629263971 @default.
- W2562926397 hasOpenAccess W2562926397 @default.
- W2562926397 hasPrimaryLocation W25629263971 @default.
- W2562926397 hasRelatedWork W1978113770 @default.
- W2562926397 hasRelatedWork W2001284764 @default.
- W2562926397 hasRelatedWork W2019522166 @default.
- W2562926397 hasRelatedWork W2030517993 @default.
- W2562926397 hasRelatedWork W2069003420 @default.
- W2562926397 hasRelatedWork W2074407850 @default.
- W2562926397 hasRelatedWork W2081626155 @default.
- W2562926397 hasRelatedWork W2105371485 @default.
- W2562926397 hasRelatedWork W2139141601 @default.
- W2562926397 hasRelatedWork W2140335535 @default.
- W2562926397 hasRelatedWork W2188080712 @default.
- W2562926397 hasRelatedWork W2325341061 @default.
- W2562926397 hasRelatedWork W2332829828 @default.
- W2562926397 hasRelatedWork W2403500327 @default.
- W2562926397 hasRelatedWork W2550521968 @default.
- W2562926397 hasRelatedWork W2586711609 @default.
- W2562926397 hasRelatedWork W2921035378 @default.
- W2562926397 hasRelatedWork W2981036811 @default.
- W2562926397 hasRelatedWork W877164126 @default.
- W2562926397 hasRelatedWork W2182500942 @default.
- W2562926397 isParatext "false" @default.
- W2562926397 isRetracted "false" @default.
- W2562926397 magId "2562926397" @default.
- W2562926397 workType "article" @default.