Proteasome inhibitors in the treatment of multiple myeloma. Leukemia

The University of Texas M. D. Anderson Cancer Center, Department of Lymphoma & Myeloma, Division of Cancer Medicine, Houston, TX, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 10/2009; 23(11):1964-79. DOI: 10.1038/leu.2009.173
Source: PubMed


Targeting intracellular protein turnover by inhibiting the ubiquitin-proteasome pathway as a strategy for cancer therapy is a new addition to our chemotherapeutic armamentarium, and has seen its greatest successes against multiple myeloma. The first-in-class proteasome inhibitor, bortezomib, was initially approved for treatment of patients in the relapsed/refractory setting as a single agent, and was recently shown to induce even greater benefits as part of rationally designed combinations that overcome chemoresistance. Modulation of proteasome function is also a rational approach to achieve chemosensitization to other antimyeloma agents, and bortezomib has now been incorporated into the front-line setting. Bortezomib-based induction regimens are able to achieve higher overall response rates and response qualities than was the case with prior standards of care, and unlike these older approaches, maintain efficacy in patients with clinically and molecularly defined high-risk disease. Second-generation proteasome inhibitors with novel properties, such as NPI-0052 and carfilzomib, are entering the clinical arena, and showing evidence of antimyeloma activity. In this spotlight review, we provide an overview of the current state of the art use of bortezomib and other proteasome inhibitors against multiple myeloma, and highlight areas for future study that will further optimize our ability to benefit patients with this disease.

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    • "Consequences of proteasome inhibition leading to toxicity include the accumulation of proteasome substrates and the failure to recycle amino acids (Suraweera et al., 2012). Intriguingly, multiple myeloma (MM) cells are hypersensitive to proteasome inhibition, and two inhibitors of the proteolytic activity of the 20S core, bortezomib and carfilzomib, have been approved for the treatment of MM patients (Shah and Orlowski, 2009; Buac et al., 2013; R ¨ ollig et al., 2014). The basis for the hypersensitivity of MM cells to proteasome inhibitors is unclear. "
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    ABSTRACT: eLife digest Cells have several mechanisms for removing proteins that have been damaged or are no longer needed. One of these mechanisms is carried out by a large protein complex called the proteasome. Drugs that block the proteasome are toxic to all cells, and a type of blood cancer called multiple myeloma is particularly sensitive to these ‘proteasome inhibitors’. However, tumors in patients with multiple myeloma can also become resistant to these drugs. Using a genetic approach, Acosta-Alvear et al. identified the factors that control the sensitivity of cells to proteasome inhibitors. In particular, reducing the levels of other factors that contribute to protein balance made the cells more sensitive. Using a combination of proteasome inhibitors and drugs that target these other factors could prove to be useful in the fight against multiple myeloma. The proteasome complex contains two types of subunits: regulatory subunits that recognize the proteins that need to be degraded, and catalytic subunits that degrade the proteins. The results of Acosta-Alvear et al. revealed how varying the levels of these two subunits influenced the sensitivity of cells to inhibitors. While decreasing the levels of catalytic subunits made the cells more sensitive, as expected, decreasing the level of regulatory subunits surprisingly made the cells resistant to the inhibitors. A possible explanation for this paradoxical result is that certain proteins are less effectively degraded by the proteasome in these cells, and that the buildup of these proteins protects the cells against the drugs. Acosta-Alvear et al. also found that lower levels of regulatory subunits desensitized multiple myeloma patients to therapy based on proteasome inhibition, suggesting that results from the genetic screen carried out in cells can predict clinical resistance mechanisms and guide the development of future therapies to increase patient survival. DOI:
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    • "Novel drug classes such as proteasome inhibitors and immunomodulatory agents have had a significant impact upon the natural history of this disease, with some studies suggesting a doubling in the median overall survival [4], [5], [6], [7], [8], [9]. Bortezomib and carfilzomib are the currently approved proteasome inhibitors for multiple myeloma, and exert their effects by blocking the turnover of poly-ubiquitinated proteins through the proteasome, which is the final effector of the ubiquitin-proteasome pathway [10], [11], [12]. Downstream effects of proteasome inhibition include activation of the endoplasmic reticulum stress response, inhibition of adherence and survival signaling through nuclear factor kappa B [10], [11], [12], and induction of a pro-apoptotic program, including through p53 [13], [14], [15], [16], [17]. "
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    ABSTRACT: Intracellular proteolytic pathways have been validated as rational targets in multiple myeloma with the approval of two proteasome inhibitors in this disease, and with the finding that immunomodulatory agents work through an E3 ubiquitin ligase containing Cereblon. Another E3 ligase that could be a rational target is the murine double minute (MDM) 2 protein, which plays a role in p53 turnover. A novel inhibitor of this complex, MI-63, was found to induce apoptosis in p53 wild-type myeloma models in association with activation of a p53-mediated cell death program. MI-63 overcame adhesion-mediated drug resistance, showed anti-tumor activity in vivo, enhanced the activity of bortezomib and lenalidomide, and also overcame lenalidomide resistance. In mutant p53 models, inhibition of MDM2 with MI-63 also activated apoptosis, albeit at higher concentrations, and this was associated with activation of autophagy. When MI-63 was combined with the BH3 mimetic ABT-737, enhanced activity was seen in both wild-type and mutant p53 models. Finally, this regimen showed efficacy against primary plasma cells from patients with newly diagnosed and relapsed/refractory myeloma. These findings support the translation of novel MDM2 inhibitors both alone, and in combination with other novel agents, to the clinic for patients with multiple myeloma.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Proteasome inhibitor bortezomib, which inhibits NF-κB activation, has been widely been used to treat MM patients worldwide [41]. Therefore, the natural products that inhibit NF-κB activation could be the novel potential agents for the treatment of MM [42]. "
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    ABSTRACT: Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB) was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX), a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.
    Full-text · Article · Apr 2014 · PLoS ONE
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