Efficacy of Bortezomib as First-Line Treatment for Patients with Multiple Myeloma

Painuly, Utkarsh; Kumar, Shaji

doi:10.4137/cmo.s7764

Cited by 22 publications

(27 citation statements)

References 122 publications

(159 reference statements)

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“…Among the proteins degraded by the ubiquitin-proteasome pathway are cyclins (A, B, D and E), cyclin-dependent kinase inhibitors such as p21 and p27, the tumor suppressor p53 and the oncoprotein c-Myc [2,3,6,27]. Decreased degradation and increased accumulation of these proteins may disrupt cell cycle progression [2,3,6,27].…”

Section: Resultsmentioning

confidence: 99%

“…Its specific 26S proteasome inhibitory function has been attributed to the reversible but strong covalent bond formed between its dipeptidyl boronic acid moiety and the threonine proteases of the 20S subunit [1–7]. Bortezomib thus effectively inhibits the ubiquitin-proteasome pathway (UPP), which is essential in regulating the homeostasis of proteins controlling cell cycle progression, survival and apoptosis [1–6]. Evidence accumulated in the literature reveals that bortezomib exhibits complex mechanisms of action in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…Evidence accumulated in the literature reveals that bortezomib exhibits complex mechanisms of action in cancer cells. These include inhibition of canonical NF-κB activation, suppression of cyclins and c-Myc, up-regulation of inhibitors of cell cycle progression (such as p21, p27, and p53), down-regulation or cleavage of anti-apoptotic proteins of the Bcl-2 family (such as Bcl-2, Bcl-xL, Mcl-1, and A1/bfl), and induction of pro-apoptotic proteins of the Bcl-2 family (such as Bim, Bid, Noxa, and Puma) [1–6]. Notably, bortezomib may target different oncogenic pathways in different cellular contexts, depending on the cancer cell type and the critical genetic alterations of each specific cancer [1–6].…”

Section: Introductionmentioning

confidence: 99%

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Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

et al. 2016

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Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

et al. 2016

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“…Bortezomib is a proteasome inhibitor, and is clinically approved as Velcade for the treatment of multiple myeloma and mantle cell lymphoma (27,28). Bortezomib can directly or indirectly affect signaling and apoptosis induction by TRAIL at multiple levels, including upregulation of TRAIL receptors 1 and 2 and modulation of the expression or activity of proapoptotic as well as antiapoptotic molecules (29).…”

Section: Discussionmentioning

confidence: 99%

Tetravalent Antibody–scTRAIL Fusion Proteins with Improved Properties

Seifert

Plappert

Fellermeier

et al. 2014

Molecular Cancer Therapeutics

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We applied the immunoglobulin E (IgE) heavy-chain domain 2 (EHD2) as the covalently linked homodimerization module to generate antibody-scTRAIL fusion proteins. By fusing a humanized single-chain fragment variable (scFv) directed against EGFR to the N-terminus of the EHD2 and a single-chain derivative of TRAIL (scTRAIL) to the C-terminus of the EHD2, we produced a dimeric, tetravalent fusion protein. The fusion protein retained its binding activity for EGFR and TRAIL receptors. In vitro, the targeted antibody-scTRAIL fusion protein exhibited an approximately 8-to 18-fold increased cytotoxic activity compared with the untargeted EHD2-scTRAIL fusion protein. This resulted in increased antitumor activity in a subcutaneous Colo205 xenograft tumor murine model. In summary, the scFv-EHD2-scTRAIL fusion protein combines target cell selectivity with an increased TRAIL activity leading to improved antitumor activities.

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“…Evidencia támogatja a FISH-eredmények használatát a terápia meghatározásánál: vannak alcsoportok, amelyek imidekre (hiperdiploid) és vannak, amelyek bortezomibra [t(4;14) és kisebb mértékben del(17p)] reagál-nak jobban [39,41].…”

Section: Javasolt Protokollok Első Vonalbanunclassified

A myeloma multiplex megközelítése Magyarországon 2016-ban

et al. 2016

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A myeloma multiplex kezelése az elmúlt évtizedben óriásit változott. Mind a kemoterápiás protokollok, mind a szupportív kezelés nagy fejlődésen ment át, amióta a legutóbbi magyar ajánlás megjelent. A betegek egyre nagyobb része ér el tartós választ, és mind többük számára van talán esély a gyógyulásra is. Az összefoglaló célja, hogy az utóbbi évek eredményeit is beépítve, az érvényes nemzetközi ajánlásokat a magyar viszonyok sajátosságaihoz adaptálva segítse a betegek leghatékonyabb kezelését. Orv. Hetil., 2016, 157(4), 123-137.Kulcsszavak: myeloma multiplex, autológ őssejt-transzplantáció, bortezomib, lenalidomid, irányelv Management of multiple myeloma in Hungary in 2016The last decade has witnessed a dramatic progress in the treatment of multiple myeloma. Both the chemotherapy protocols and the supportive therapy options have improved significantly since the publication of the previous Hungarian national guideline. An increasing proportion of patients now reach a durable response and cure became a potential option for some. The aim of the authors was to adapt the international guidelines to the specific circumstances of the Hungarian healthcare system in the light of the most recent developments.

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Efficacy of Bortezomib as First-Line Treatment for Patients with Multiple Myeloma

Cited by 22 publications

References 122 publications

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

Tetravalent Antibody–scTRAIL Fusion Proteins with Improved Properties

A myeloma multiplex megközelítése Magyarországon 2016-ban

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