Regulation of OSU-03012 Toxicity by ER Stress Proteins and ER Stress–Inducing Drugs

Booth, Laurence; Roberts, Jeanette C.; Cruickshanks, Nichola; Grant, Steven; Poklepovic, Andrew; Dent, Paul

doi:10.1158/1535-7163.mct-14-0172

Cited by 41 publications

(64 citation statements)

References 56 publications

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“…Sildenafil and celecoxib treatment also inhibited the growth of mammary tumors in vivo which was enhanced by the multiple sclerosis drug FTY720 (Fingolimod, Gilenya) that is known to suppress sphingosine-1-phosphate (S1P) signaling through S1P production and increasing the ceramide levels (Booth et al, 2014c). Sildenafil and tadalafil were also shown to interact with non-coxib celecoxib derivative OSU-03012 (lacking COX2-inhibitory activity) in killing of glioblastoma multiforme (GBM) cells by recruiting death receptor signaling (Booth et al, 2014b). …”

Section: Pde5 Inhibitors In Cancermentioning

confidence: 99%

“…In recent years, there has been tremendous interest in identifying new clinical uses of PDE5 inhibitors in various ailments including cardiovascular disease (Kukreja et al, 2004; Kukreja et al, 2005; Kukreja et al, 2011), diabetes (Giannetta et al, 2012; Koka et al, 2012; Koka et al, 2013; Koka et al, 2014; Varma et al, 2012) and cancer (Black et al, 2008; Booth et al, 2014a; Booth et al, 2014c; Booth et al, 2014b; Das et al, 2010; Hamilton et al, 2013; Resnick et al, 2009; Roberts et al, 2014). Today, close to 100 clinical trials (http://www.clinicaltrials.gov) with PDE5 inhibitors focusing on the potential cardiovascular benefits have been completed or are ongoing.…”

Section: Introductionmentioning

confidence: 99%

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PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

Das

Durrant

Salloum

et al. 2015

Pharmacology & Therapeutics

192

150

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The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and cancer benefits. Despite mixed results of these clinical trials, there is continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients.

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Section: Pde5 Inhibitors In Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

Das

Durrant

Salloum

et al. 2015

Pharmacology & Therapeutics

192

150

View full text Add to dashboard Cite

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“…Although activation of the death receptor CD95 could play a role in the drug interactions, other data argued that prolonged high levels of autophagosome formation also were essential for the lethal synergistic combination effects with the PDE5 inhibitor [1–4]. …”

Section: Introductionmentioning

confidence: 99%

“…Other studies then linked the effects of AR-12 on tumor cell biology to the regulation of chaperone proteins [4, 5]. In more recent studies, we have shown that sorafenib, pazopanib, AR-12 and regorafenib can reduce the apparent expression chaperone proteins HSP90, GRP78 and HSP70 using an in-cell western/immuno-fluorescence approach [5–12].…”

Section: Introductionmentioning

confidence: 99%

Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cellsin vitroandin 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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“…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].…”

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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Regulation of OSU-03012 Toxicity by ER Stress Proteins and ER Stress–Inducing Drugs

Cited by 41 publications

References 56 publications

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cellsin vitroandin vivo

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

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