ArticleOncotarget2016
Multi-kinase inhibitors can associate with heat shock proteins through their NH2-termini by which they suppress chaperone function.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 48 citations in OpenAlex.
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- Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents.International journal of molecular sciences · 2023Review
- Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management.Journal of translational medicine · 2022Review
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- Canine osteosarcoma cells exhibit basal accumulation of multiple chaperone proteins and are sensitive to small molecule inhibitors of GRP78 and heat shock protein function.Cell stress & chaperones · 2022Article
- Combination treatment with sorafenib and wh-4 additively suppresses the proliferation of liver cancer cells.Experimental and therapeutic medicine · 2022Article
- Article
- AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication.Biochemical pharmacology · 2020Article
- GZ17-6.02 and Doxorubicin Interact to Kill Sarcoma Cells via Autophagy and Death Receptor Signaling.Frontiers in oncology · 2020Article
- Not the comfy chair! Cancer drugs that act against multiple active sites.Expert opinion on therapeutic targets · 2019Review
- Neratinib augments the lethality of [regorafenib + sildenafil].Journal of cellular physiology · 2019Article
- Kinase inhibitors: look beyond the label on the bottle.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib.Frontiers in oncology · 2019Article
- The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy.Antiviral research · 2018Article
- Glucose-regulated protein 78 substrate-binding domain alters its conformation upon EGCG inhibitor binding to nucleotide-binding domain: Molecular dynamics studies.Scientific reports · 2018Article
- Protein biosynthesis, a target of sorafenib, interferes with the unfolded protein response (UPR) and ferroptosis in hepatocellular carcinoma cells.Oncotarget · 2018Article
- Curcumin interacts with sildenafil to kill GI tumor cells via endoplasmic reticulum stress and reactive oxygen/ nitrogen species.Oncotarget · 2017Article
- Sorafenib Impedes Rift Valley Fever Virus Egress by Inhibiting Valosin-Containing Protein Function in the Cellular Secretory Pathway.Journal of virology · 2017Article
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Authors and funding
13 authors at 7 institutions in 2 countries.
Funding
Abstract
We performed proteomic studies using the GRP78 chaperone-inhibitor drug AR-12 (OSU-03012) as bait. Multiple additional chaperone and chaperone-associated proteins were shown to interact with AR-12, including: GRP75, HSP75, BAG2; HSP27; ULK-1; and thioredoxin. AR-12 down-regulated in situ immuno-fluorescence detection of ATP binding chaperones using antibodies directed against the NH2-termini of the proteins but only weakly reduced detection using antibodies directed against the central and COOH portions of the proteins. Traditional SDS-PAGE and western blotting assessment methods did not exhibit any alterations in chaperone detection. AR-12 altered the sub-cellular distribution of chaperone proteins, abolishing their punctate speckled patterning concomitant with changes in protein co-localization. AR-12 inhibited chaperone ATPase activity, which was enhanced by sildenafil; inhibited chaperone - chaperone and chaperone - client interactions; and docked in silico with the ATPase domains of HSP90 and of HSP70. AR-12 combined with sildenafil in a GRP78 plus HSP27 -dependent fashion to profoundly activate an eIF2α/ATF4/CHOP/Beclin1 pathway in parallel with inactivating mTOR and increasing ATG13 phosphorylation, collectively resulting in formation of punctate toxic autophagosomes. Over-expression of [GRP78 and HSP27] prevented: AR-12 -induced activation of ER stress signaling and maintained mTOR activity; AR-12 -mediated down-regulation of thioredoxin, MCL-1 and c-FLIP-s; and preserved tumor cell viability. Thus the inhibition of chaperone protein functions by AR-12 and by multi-kinase inhibitors very likely explains why these agents have anti-tumor effects in multiple genetically diverse tumor cell types.
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Registered trials
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