Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD<sup>®</sup>immunomodulatory drug pomalidomide

Das, Deepika Sharma; Ray, Arghya; Song, Yan; Richardson, Paul G.; Trikha, Mohit; Chauhan, Dharminder; Anderson, Kenneth C.

doi:10.1111/bjh.13780

Cited by 41 publications

(23 citation statements)

References 58 publications

(72 reference statements)

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“…29,41,42 Specifically, we showed that pDCs are relatively resistant to novel and conventional therapies; protect tumor cells from therapy-induced cytotoxicity; promote tumor growth and survival; as well as suppress immune responses. 29,41,42 We therefore next examined the effect of RA190 on pDC-induced MM cell growth. MM.1S cells and patient pDCs were cultured either alone or together.…”

Section: Resultsmentioning

confidence: 99%

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Song

Ray

et al. 2016

Leukemia

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Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability. A novel agent RA190 targets Rpn13 and inhibits proteasome function, without blocking the proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13. RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes bortezomib resistance. Anti-MM activity of RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that RA190 is well tolerated, inhibits tumor growth and prolongs survival. Combining RA190 with bortezomib, lenalidomide or pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM.

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Section: Resultsmentioning

confidence: 99%

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Song

Ray

et al. 2016

Leukemia

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“…Cell cycle analysis was performed as described previously 15 . Cell viability was assessed by WST-1/CellTiter-Glo (CTG) Luminescent assays, as in prior study 16 .…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting was performed as previously described 15 using antibodies against USP1, USP2, USP5, USP7, USP14, Caspase-3/8/9, p21, FANCD2, FANCI, PCNA, Rad51, GAPDH (Cell Signaling, Beverly, MA, USA); ID1, ID2, ID3, ID4, Notch-1, Notch-2, Sox-4 and Sox-2 (Bethyl Laboratories, Montgomery, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells

Das

Ray

et al. 2017

Clinical Cancer Research

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Purpose The ubiquitin proteasome pathway is a validated therapeutic target in multiple myeloma (MM). Deubiquitylating enzyme USP1 participates in DNA damage response and cellular differentiation pathways. To date, the role of USP1 in MM biology is not defined. In the present study, we investigated the functional significance of USP1 in MM using genetic and biochemical approaches. Experimental Design To investigate the role of USP1 in myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies in myeloma cell lines and patient MM cells. Results USP1-siRNA knockdown decreases MM cell viability. USP1 inhibitor SJB selectively blocks USP1 enzymatic activity without blocking other DUBs. SJB also decreases the viability of MM cell lines and patient tumor cells, inhibits bone marrow plasmacytoid dendritic cells-induced MM cell growth and overcomes bortezomib-resistance. SJB triggers apoptosis in MM cells via activation of caspase-3, caspase-8 and caspase-9. Moreover, SJB degrades USP1 and downstream inhibitor of DNA binding proteins, as well as inhibits DNA repair via blockade of Fanconi anemia pathway and homologous recombination. SJB also downregulates MM stem cell renewal/survival-associated proteins Notch-1, Notch-2, SOX-4 and SOX-2. Moreover, SJB induced generation of more mature and differentiated plasma cells. Combination of SJB and HDACi ACY-1215, bortezomib, lenalidomide, or pomalidomide triggers synergistic cytotoxicity. Conclusions Our preclinical studies provide the framework for clinical evaluation of USP1 inhibitors, alone or in combination, as a potential novel MM therapy.

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“…Cell viability was assessed by WST-1/CellTiter-Glo Luminescent assays, as previously described 22,23 . DNA synthesis was measured by 3 H-TdR uptake.…”

Section: Methodsmentioning

confidence: 99%

A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells

et al. 2016

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The hypoxic bone-marrow (BM) microenvironment confers growth/survival and drug-resistance in multiple myeloma (MM) cells. Novel therapies targeting the MM cell in its hypoxic-BM milieu may overcome drug resistance. Recent studies led to the development of a novel molecule RRx-001 with hypoxia-selective epigenetic and Nitric Oxide-donating properties. Here we demonstrate that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug-resistance. RRx-001 inhibits MM cell growth in the presence of BM stromal cells. RRx-001 induced apoptosis is associated with: 1) activation of caspases; 2) release of ROS and nitrogen-species; 3) induction of DNA damage via ATM/γ-H2AX; and 4) decrease in DNA methytransferase (DNMT) and global methylation. RNA interference study shows a predominant role of DNMT1 in MM cell survival versus DNMT3a or DNMT3b. Deubiquitylating enzyme USP7 stimulates DNMT1 activity; and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. RRx-001 plus USP7 inhibitor P5091 triggered synergistic anti-MM activity. MM xenograft studies show that RRx-001 is well tolerated, inhibits tumor growth, and enhances survival. Combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity. Our results provide the rationale for translation of RRx-001, either alone or in combination, to clinical evaluation in MM.

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Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD^®immunomodulatory drug pomalidomide

Cited by 41 publications

References 58 publications

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells

A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells

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Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD®immunomodulatory drug pomalidomide

Cited by 41 publications

References 58 publications

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells

A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells

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Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD^®immunomodulatory drug pomalidomide