Bortezomib Mediates Antiangiogenesis in Multiple Myeloma via Direct and Indirect Effects on Endothelial Cells

Roccaro, Aldo M.; Hideshima, Teru; Raje, Noopur; Kumar, Santosh; Ishitsuka, Kenji; Yasui, Hiroshi; Shiraishi, Norihiko; Ribatti, Doménico; Nico, Beatrice; Vacca, Angelo; Dammacco, Franco; Richardson, Paul G.; Anderson, Kenneth C.

doi:10.1158/0008-5472.can-05-1195

Cited by 262 publications

(221 citation statements)

References 42 publications

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“…Inhibition of angiogenesis with bevacizumab, sunitinib, cyclic arginine-glycine-aspartic (cRGD) peptide or mammalian target of rapamycin (mTOR) inhibitors has been reported to enhance the anti-tumor effects of oncolytic viruses (Homicsko et al, 2005;Kurozumi et al, 2007;Libertini et al, 2008;Kottke et al, 2010). Since bortezomib inhibits nuclear factor kB activity, reduces vascular endothelial growth factor (VEGF) levels and decreases angiogenesis (Sunwoo et al, 2001;Nawrocki et al, 2002;Roccaro et al, 2006), modulation of vascular permeability may also account for some of the promising activity observed in vivo with the Reolysin/bortezomib combination. However, our data demonstrate that stimulation of ER stress and NOXA expression by Reolysin significantly contributes to its ability to enhance bortezomib's anti-myeloma activity.…”

Section: Discussionmentioning

confidence: 99%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA. Knockdown of NOXA expression by short hairpin RNA significantly reduced the pro-apoptotic effects of Reolysin. We next showed that co-administration of Reolysin and bortezomib resulted in the dual accumulation of viral and ubiquitinated proteins, which led to enhanced ER stress, NOXA induction and apoptosis. Importantly, the combination of reovirus infection and proteasomal inhibition significantly decreased tumor burden in a xenograft and syngeneic bone disease model of MM without exhibiting adverse side effects. Our study establishes ER stress stimulation and NOXA induction as novel mediators of reovirus-induced apoptosis. Furthermore, reovirus infection can be used as a promising approach to augment the anti-myeloma activity of bortezomib by promoting additional stress to the endoplasmic reticulum of MM cells.

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Section: Discussionmentioning

confidence: 99%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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“…18 Of particular interest is the recent observation that terminally differentiated immunoglobulin (Ig)-secreting plasma cells would have impaired proteasome activity. 19 The reduced proteolytic capacity is accompanied by accumulation of polyubiquitinated proteins, stabilization of substrates such as Ik-Ba and Bax, apoptosis induction and sensitization to proteasome inhibitors.…”

Section: Mechanisms Of Anticancer Activity Of Proteasome Inhibitorsmentioning

confidence: 99%

Proteasome inhibitors: antitumor effects and beyond

et al. 2006

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Proteasome inhibitors are emerging as effective drugs for the treatment of multiple myeloma and possibly certain subtypes of non-Hodgkin's lymphoma. Bortezomib (Velcade) is the first proteasome inhibitor proven to be clinically useful and will soon be followed by a second generation of small molecule inhibitors with improved pharmacological properties. Although it is now understood that certain types of malignancies have an exquisite dependence on a functional proteasome for their survival, the underlying reason(s) remain unclear as of now. In this context, addiction to nuclear factor-jB (NF-jB)-induced survival signals, activation of the unfolded protein response as well as a reduced proteasomal activity in differentiated plasma cells have all been proposed to justify proteasome inhibitors' activity in susceptible tissues. The ubiquitin-proteasome pathway and its relevance to cancerThe ubiquitin-proteasome pathway (UPP) mediates the degradation of polyubiquitinated proteins and represents the main protein degradation pathway in eucaryotic cells. 1 It is estimated that more than 80% of intracellular proteins are degraded by the proteasome. Besides carrying out protein turnover, the UPP plays an essential role in regulating protein levels during cell cycle, apoptosis, response to cellular stress (i.e. DNA damage, hypoxia) and intracellular signal transduction, not to mention its importance for the generation of antigenic epitopes to be presented on human leukocyte antigen (HLA) molecules. It is now known that some types of cancer are exquisitely prone to undergo apoptosis in response to inhibition of the UPP pathway, a phenomenon that, at present, still lacks a precise explanation. 2,3 Intracellular proteins are targeted for degradation by the conjugation of polyubiquitin chains to lysine residues of the protein, a process carried out by ubiquitin-conjugating enzymes and antagonized by deubiquitinating proteases (revised by Nijman et al. 4 ). 1 Ubiquitination is performed by three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). E1 activates ubiquitin monomers by adenylation and transfers them to E2, which in turn works in conjunction with E3 to confer substrate specificity. Whereas E1 only exists in two isoforms derived from alternative splicing of the same messenger at least 25 E2 and hundreds of E3 enzymes exist. 1 A similar complexity is shared by the deubiquitinating enzymes, of which more than 500 are represented in the human genome, thus indicating the high complexity and specificity of this regulatory mechanism. 4 The proteasome is an enzymatic complex that recognizes ubiquitin-tagged proteins and catalyses their proteolytic degradation in an ATP-dependent fashion. 1-3 Proteasomes can be found both in the cytoplasm and in the nucleus of eucaryotic cells. The proteasome typically consists of a 20S component, which is normally associated to a 19S or to an 11S (inducible by interferon-g) regulator component. The 20S proteasome component is compris...

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“…The antiangiogenic effect of bortezomib is another potential mechanism of its anti-MM activity (Le Blanc et al, 2002;Roccaro et al, 2006). Moreover, bortezomib downregulates caveolin-1 expression and inhibits caveolin-1 tyrosine phosphorylation, which are required for VEGFmediated MM cell migration on fibronectin, and blocks VEGF-induced tyrosine phosphorylation of caveolin-1 in HUVEC, thereby inhibiting ERK-dependent EC proliferation (Podar and Anderson, 2005).…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

2006

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Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

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Bortezomib Mediates Antiangiogenesis in Multiple Myeloma via Direct and Indirect Effects on Endothelial Cells

Abstract: Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma.

Cited by 262 publications

References 42 publications

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

Proteasome inhibitors: antitumor effects and beyond

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

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