Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease

García-Gómez, Antonio; Quwaider, Dalia; Canavese, Miriam; Ocio, Enrique M.; Tian, Ze; Blanco, Juan F.; Berger, Allison; Ortiz‐de‐Solórzano, Carlos; Hernández-Iglesias, Teresa; Martens, Anton C.; Groen, Richard W.J.; Mateo-Urdiales, Joaquín; Fraile, Susana; Galarraga, M.M. Bruno; Chauhan, Dharminder; Miguel, Jesús F. San; Raje, Noopur; Garayoa, Mercedes

doi:10.1158/1078-0432.ccr-13-1657

Cited by 72 publications

(70 citation statements)

References 49 publications

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“…Namely, the proteasome inhibitor bortezomib (BTZ), which blocks the degradation of polyubiquitinated misfolded proteins, induces ER stress, and triggers apoptosis of MM cells, has rapidly translated to clinical trials demonstrating remarkable clinical efficacy. The second-generation proteasome inhibitors carfilzomib (CFZ) (2), ixazomib (3), and marizomib (4) also are showing improved pharmacological properties and promising responses. Nonetheless, MM cells develop resistance to BTZ, leading to relapse of disease in most patients (5,6).…”

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confidence: 99%

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Hideshima

Paranal

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility.Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.histone deacetylase 6 | proteasome inhibitor | multiple myeloma | bortezomib-resistance | WT161

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confidence: 99%

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Hideshima

Paranal

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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“…The MM.1S-luc cell line was kindly provided by Dr. Mitsiades (Dana-Farber Cancer Institute, Boston, MA), whereas RPMI-8226-luc was lentivirally transduced to express firefly luciferase. 28 Measurement of IL-8 in Culture Medium MM.1S, H929, JJN3, OPM2, U266, RPMI-8226, and IM9 (2 Â 10 5 cells/mL) were cultured for 3 days. The supernatants were collected and analyzed for IL-8 expression using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (R&D Systems, Minneapolis, MN), according to manufacturer's instructions.…”

Section: Cells and Culture Conditionsmentioning

confidence: 99%

Effects of IL-8 Up-Regulation on Cell Survival and Osteoclastogenesis in Multiple Myeloma

Herrero

García-Gómez

Garayoa

et al. 2016

The American Journal of Pathology

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IL-8 promotes cancer cell growth, survival, angiogenesis, and metastasis in several tumors. Herein, we investigated the sources of IL-8 production in multiple myeloma (MM) and its potential roles in MM pathogenesis. We found that bone marrow cells from patients with MM secreted higher amounts of IL-8 than healthy donors. IL-8 production was detected in cultures of CD138(+) plasma cells and CD138(-) cells isolated from bone marrows of MM patients, and in three of seven human myeloma cell lines (HMCLs) analyzed. Interactions between MM and stromal cells increased IL-8 secretion by stromal cells through cell-cell adhesion and soluble factors. Interestingly, IL8 expression also increased in HMCLs, stromal cells, and osteoclasts after treatment with the antimyeloma drugs melphalan and bortezomib. In fact, the effect of bortezomib on IL-8 production was higher than that exerted by stromal-MM cell interactions. Addition of exogenous IL-8 did not affect growth of HMCLs, although it protected cells from death induced by serum starvation through a caspase-independent mechanism. Furthermore, IL-8 induced by stromal-MM cell interactions strongly contributed to osteoclast formation in vitro, because osteoclastogenesis was markedly reduced by IL-8-specific neutralizing antibodies. In conclusion, our results implicate IL-8 in myeloma bone disease and point to the potential utility of an anti-IL-8 therapy to prevent unwanted effects of IL-8 up-regulation on survival, angiogenesis, and osteolysis in MM.

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“…Подобно другим ингибиторам про-теасомы, иксазомиб ингибирует остеокластогенез и опу-холевую резорбцию костной ткани за счет блокирования RANKL (цитокин семейства факторов некроза опухоли), являющегося ключевым фактором дифференцировки и активации остеокластов, дезинтеграции F-актина и сниже-ния экспрессии интегрина aVb3 [15].…”

Section: таблица 1 сравнительная характеристика одобренных ингибиторunclassified

Ixazomib in the treatment of relapsed multiple myeloma

Семочкин¹

2018

Med. sov.

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Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease

Cited by 72 publications

References 49 publications

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Effects of IL-8 Up-Regulation on Cell Survival and Osteoclastogenesis in Multiple Myeloma

Ixazomib in the treatment of relapsed multiple myeloma

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