GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases

Roberts, Jeanette C.; Tavallai, Mehrad; Nourbakhsh, Aida; Fidanza, Abigail; Cruz-Luna, Tanya; Smith, E. L.; Siembida, Paul; Plamondon, Pascale; Cycon, Kelly A.; Doern, Christopher D.; Booth, Laurence; Dent, Paul

doi:10.1002/jcp.25014

Cited by 56 publications

(64 citation statements)

References 117 publications

(125 reference statements)

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“…The role of HSP27 in the regulation of other PI3K pathway regulated processes also connects our prior studies with [sorafenib/regorafenib + sildenafil] to the new data in this manuscript [6, 8]. As GRP78 and HSP27 both act to maintain PI3K/AKT signaling they also could be thought to very likely play a key role in the regulation of the PI3K-regulated kinase mTOR.…”

Section: Discussionsupporting

confidence: 78%

“…From our prior studies in Tavallai et al and Roberts et al we also were aware that tumors treated with [sorafenib/regorafenib + sildenafil] re-grow after therapy with higher ERBB1 phosphorylation and that the combination of [sorafenib/regorafenib + sildenafil] can reduce the detection by in-cell western/immuno-fluorescence of the chaperones HSP90, GRP78 and HSP70 [6, 8]. The “big-picture” conclusions we had previously made concerning the biology of the [sorafenib/regorafenib + sildenafil] drug combination prior to the present manuscript were that the combination kills tumor cells selectively over non-transformed cells and does so by primarily inactivating and down-regulating anti-apoptotic protein expression together with those of chaperones which causes both death receptor activation and mitochondrial dysfunction as well as a prolonged intense endoplasmic reticulum stress response leading to high levels of autophagy flux and an apparent necroptotic form of tumor cell death.…”

Section: Discussionmentioning

confidence: 99%

“…HSP90, have been the target for many developmental therapeutic chemists and also tumor cell biology researchers [15, 16]. Based on the fact our cancer biology data with chaperones and OSU-03012, sorafenib, pazopanib and regorafenib was congruent with the wider literature exploring the roles of chaperones in virus biology, we recently performed studies to determine whether these drugs could alter virus reproduction in vitro [7, 8]. In these studies, we discovered that OSU-03012, pazopanib or sorafenib all exhibited strong anti-viral properties against a wide range of DNA and RNA viruses [17].…”

Section: Introductionmentioning

confidence: 99%

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Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo

et al. 2016

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We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] –dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo, respectively.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo

et al. 2016

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“…The enhanced killing effect of the drug combination was associated with enhanced PERK-dependent ER stress signaling and autophagosome formation, as well as through death receptor activation [6]. Congruent data were obtained using the parent drug of OSU-03012, celecoxib, and also with the multi-kinase inhibitors sorafenib, regorafenib and pazopanib [7,8]. These pre-clinical studies have resulted in two open clinical trials; in all solid tumor patients (NCT02466802) where patients are receiving increasing once daily dosing with regorafenib and sildenafil; in recurrent glioblastoma patients (NCT01817751) where they receive sorafenib, sildenafil and valproate twice daily.…”

Section: Commentarymentioning

confidence: 99%

“…From this realization we have performed studies to determine whether OSU-03012 could alter virus reproduction. OSU-03012 and the multi-kinase inhibitors sorafenib (Nexavar) and pazopanib (Votrient) reduced the expression of multiple chaperones in the HSP70 family and the HSP90 family; effects that were magnified by the PDE5 inhibitor sildenafil [7,22,23]. And, because our drug combinations were inhibiting the chaperone function of many diverse chaperones, we found that OSU-03012 or sorafenib or pazopanib could strongly inhibit the reproduction of antiviral a wide range of DNA and RNA viruses.…”

Section: Commentarymentioning

confidence: 99%

AR-12 Inhibits Chaperone Proteins Preventing Virus Replication and the Accumulation of Toxic Misfolded Proteins

Booth¹,

Roberts²,

Ecroyd³

et al. 2016

J Clin Cell Immunol

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CommentaryAlthough originally thought to be an inhibitor of PDK-1, OSU-03012 (AR-12) was shown in 2005 not to primarily act as a PDK-1 inhibitor in its ability to radio-sensitize tumor cells [1,2]. Subsequently it was shown that the primary mechanism by which AR-12 killed tumor cells was via the PKR-like endoplasmic reticulum kinase (PERK) -dependent induction of endoplasmic reticulum stress signaling [1][2][3]. ER stress signaling in turn promoted a toxic form of autophagy resulting in a necroptotic form of cell death.As AR-12 was causing an ER stress signal, the on-going studies became more focused on defining whether the functions and activities of chaperone proteins, particularly HSP90, HSP70 and GRP78, were being altered by the drug [3]. By western immuno-blotting, AR-12 lowered the expression of HSP90 and GRP78 but stimulated HSP70 expression. These findings were independently confirmed [4]. As AR-12 reduced expression of the PERK inhibitory chaperone GRP78, and as the induction of toxic autophagy was PERK dependent, we investigated in more detail the role of altered GRP78 expression in mediating drug toxicity. AR-12 destabilized GRP78 protein, significantly lowering its half-life as assessed by western blotting from >24 hours to 10 hours [5]. Transfection of cells with a plasmid to force over-expression of GRP78 blunted AR-12 induced PERK activation; autophagosome formation, and tumor cell death.Data published in 2014 and 2015 with AR-12 have additionally underlined the prominence of chaperones and especially GRP78 in the cell biology of OSU-03012. Phosphodiesterase 5 inhibitors including sildenafil (Viagra) and tadalafil (Cialis) were shown to interact with OSU-03012 to facilitate killing in a wide variety of tumor cells. The enhanced killing effect of the drug combination was associated with enhanced PERK-dependent ER stress signaling and autophagosome formation, as well as through death receptor activation [6]. Congruent data were obtained using the parent drug of OSU-03012, celecoxib, and also with the multi-kinase inhibitors sorafenib, regorafenib and pazopanib [7,8]. These pre-clinical studies have resulted in two open clinical trials; in all solid tumor patients (NCT02466802) where patients are receiving increasing once daily dosing with regorafenib and sildenafil; in recurrent glioblastoma patients (NCT01817751) where they receive sorafenib, sildenafil and valproate twice daily.From the research of many laboratories it has been defined that multiple chaperone proteins interact to play key roles in preserving protein stability and signaling, most notably in tumor cells which very often express much higher levels of protein than non-transformed cells. Hence some chaperones, e.g. HSP90, have become a target for developmental therapeutic synthetic chemists and also tumor cell biology scientists. In the area of viral reproductive biology, proteins such as HSPA5/ GRP78/ BiP have for almost 30 years been recognized as playing key facilitator roles in the life cycles of both DNA and RNA viruses [9][10][11...

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AR‐12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication

Booth

Roberts

Ecroyd

et al. 2016

Journal Cellular Physiology

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We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock down of chaperones or AR-12 treatment inactivated mTOR and elevated ATG13 S318 phosphorylation concomitant with inducing an endoplasmic reticulum stress response that in an eIF2α-dependent fashion increased Beclin1 and LC3 expression and autophagosome formation. Over-expression of chaperones prevented the reduction in receptor/glucosidase expression, mTOR inactivation, the ER stress response, and autophagosome formation. AR-12 reduced the reproduction of viruses including Mumps, Influenza, Measles, Junín, Rubella, HIV (wild type and protease resistant), and Ebola, an effect replicated by knock down of multiple chaperone proteins. AR-12-stimulated the co-localization of Influenza, EBV and HIV virus proteins with LC3 in autophagosomes and reduced viral protein association with the chaperones HSP90, HSP70, and GRP78. Knock down of Beclin1 suppressed drug-induced autophagosome formation and reduced the anti-viral protection afforded by AR-12. In an animal model of hemorrhagic fever virus, a transient exposure of animals to low doses of AR-12 doubled animal survival from ∼30% to ∼60% and suppressed liver damage as measured by ATL, GGT and LDH release. Thus through inhibition of chaperone protein functions; reducing the production, stability and processing of viral proteins; and stimulating autophagosome formation/viral protein degradation, AR-12 acts as a broad-specificity anti-viral drug in vitro and in vivo. We argue future patient studies with AR-12 are warranted. J. Cell. Physiol. 231: 2286-2302, 2016. © 2016 Wiley Periodicals, Inc.

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GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases

Cited by 56 publications

References 117 publications

Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo

Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo

AR-12 Inhibits Chaperone Proteins Preventing Virus Replication and the Accumulation of Toxic Misfolded Proteins

AR‐12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication

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