PCI-24781 Induces Caspase and Reactive Oxygen Species–Dependent Apoptosis Through NF-κB Mechanisms and Is Synergistic with Bortezomib in Lymphoma Cells

Bhalla, Savita; Balasubramanian, Sriram; David, Kevin A.; Sirisawad, Mint; Buggy, Joseph J.; Mauro, Lauren; Prachand, Sheila; Miller, Richard A.; Li, Gordon; Evens, Andrew M.

doi:10.1158/1078-0432.ccr-08-2365

Cited by 90 publications

(81 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The synergistic induction of apoptosis after HDACi/ BTZ treatments has been partially associated with an inhibition of NF-kB signaling in mature B-cell malignancies, myeloid leukemia, and T-ALL (9,10,13,16). These observations are consistent with the finding that NF-kB signaling is indispensable for the homeostasis of mature B cells and contributes to the survival of mature B-cell malignancies (17,18).…”

Section: Introductionsupporting

confidence: 85%

See 1 more Smart Citation

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

Bastian

Hof

Pfau

et al. 2013

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACi) with a toxicity profile differing from that of conventional cytotoxic agents, are needed for these extensively pretreated patients.Experimental Design: Antiproliferative and proapoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP-ALL monocultures, cocultures with primary mesenchymal stroma cells from patients with ALL, and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation.Results: We identified the proteasome inhibitor bortezomib as a promising combination partner for HDACi due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK, PI3K/AKT, p53, ubiquitin/proteasome, and NF-kB pathways. We observed an activation of NF-kB after bortezomib treatment and the induction of apoptosis-related NFkB target genes such as TNFaRs after concomitant treatment, indicating a possible involvement of NF-kB as proapoptotic mediator. In this context, significantly lower NF-kB subunits gene expression was detected in leukemia cells from patients who developed a relapse during frontline chemotherapy, compared with those who relapsed after cessation of frontline therapy.Conclusion: These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols.

show abstract

Section: Introductionsupporting

confidence: 85%

“…Proteasome inhibitors such as bortezomib (BTZ) were found to increase substantially the activity of HDACi in different hematologic and solid malignancies (9)(10)(11)(12)(13). To date, no systematic studies have been conducted to analyze the response of B-cell precursor leukemias to HDACi/proteasome inhibitor combinations.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

Bastian

Hof

Pfau

et al. 2013

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…3E). NK-kB activation and mitochondrial membrane potential were shown to be closely associated with ROS generation (31,32). However, according to our results, no significant change in expression of NFkB-related proteins, including p-p65, p65, and IKKa/b, was observed after treatment with combined bortezomib/SAHA when compared with either drug alone (Fig.…”

Section: Resultssupporting

confidence: 50%

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

Hui

Lam

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

A novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPC was determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G 1 , Annexin V-positive, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/ SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC. Mol Cancer Ther; 12(5); 747-58. Ó2013 AACR.

show abstract

“…[39][40][41][42] Recent clinical trials combining bortezomib and the HDAC inhibitor vorinostat showed a promising outcome in relapsed and refractory MM, including activity among some patients with prior exposure to bortezomib. 43 Another study showed that vorinostat adds to the antitumor activity of the proteasome inhibitor carfilzomib in human diffuse large B-cell lymphoma (DLBCL) cells.…”

Section: Combined Treatment With Onx 0912 and Bortezomib Dex Lenalimentioning

confidence: 99%

A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma

Chauhan

Singh

Aujay³

et al. 2010

Blood

178

121

View full text Add to dashboard Cite

Bortezomib therapy has proven successful for the treatment of relapsed, relapsed/ refractory, and newly diagnosed multiple myeloma (MM). At present, bortezomib is available as an intravenous injection, and its prolonged treatment is associated with toxicity and development of drug resistance. Here we show that the novel proteasome inhibitor ONX 0912, a tripeptide epoxyketone, inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies. IntroductionThe Ubiquitin-Proteasome Signaling (UPS) pathway regulates normal cellular processes including cell cycle, DNA replication, transcription, and cell death via proteolysis of regulatory proteins. Alterations in UPS are linked to the pathogenesis of various human diseases, 1 and therefore, targeting UPS components such as proteasomes offers great promise as a novel therapeutic strategy. Bortezomib is the first-in-class proteasome inhibitor, approved by the Food and Drug Administration for the treatment of relapsed, relapsed/refractory, and newly diagnosed multiple myeloma (MM). [1][2][3][4][5] Although bortezomib therapy is a major advance, 3,4 it has been associated with possible off-target toxicities and the development of drug resistance. 6,7 On the heels of clinical success of bortezomib, many recent studies have focused on developing other proteasome inhibitors as therapeutics in cancer. In this context, recent reports demonstrated that carfilzomib (PR-171), a structural analog of the microbial natural product epoxomicin, triggers potent antitumor activity 8,9 associated with inhibition of chymotrypsin-like (CT-L) proteasome activity. 9-12 A Phase II clinical trial of carfilzomib in relapsed-refractory MM has shown promising single agent activity, including responses in patients relapsed from or refractory to bortezomib therapy. 13 However, like bortezomib, carfilzomib is also administered intravenously in patients. More recently, an orally bioavailable analog of carfilzomib, ONX 0912, was discovered during a medicinal chemistry effort using tripeptide epoxyketones. 14 Importantly, the clinical applicability of ONX 0912 will allow for enhanced dosing flexibility and patient convenience.In the present study, we examined the antitumor activity of ONX 0912 using MM cell lines and primary patient cells, as well as animal models. ONX 0912, like carfilzomib and bortezomib, triggers marked anti-MM activity associated with inhibition of proteasome CT-L activity. In vivo studies, using 2 distinct human MM xenograft mouse models, showed that ONX 0912 is well tolerated, inhibits tumor growth, and prolongs survival in mice. The combination of ONX 0912 with bortezomib, lenalidomide, pan-histone deacetylase (HDAC) inhibitor MS-275 or dexamethasone induces synergistic/additive anti-MM activity. Current bortezomib or carfilzomib therapy requires intravenous administration, whereas ONX 0912 is orally bioactive. Overall, our preclinical data provide the framework for clinical trials of ONX 0912, either alone or in combination with other anti-M...

show abstract

PCI-24781 Induces Caspase and Reactive Oxygen Species–Dependent Apoptosis Through NF-κB Mechanisms and Is Synergistic with Bortezomib in Lymphoma Cells

Cited by 90 publications

References 38 publications

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma

Contact Info

Product

Resources

About