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: Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.08153 · 9.32 Impact Factor
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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.
    PLoS ONE 09/2014; 9(9):e103015. DOI:10.1371/journal.pone.0103015 · 3.23 Impact Factor
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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.
    PLoS ONE 04/2014; 9(4):e95846. DOI:10.1371/journal.pone.0095846 · 3.23 Impact Factor
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