Stromal cells in bone marrow play important roles in pro-inflammatory cytokine secretion causing fever following bortezomib administration in patients with multiple myeloma

Maruyama, Dai; Watanabe, Takashi; Heike, Yuji; Nagase, Kumiko; Takahashi, Noriko; Yamasaki, Satoshi; Waki, Fusako; Yokoyama, Hisayuki; Kim, Sung Won; Kobayashi, Yasuhito; Aizawa, Shin; Tobinai, Kensei

doi:10.1007/s12185-008-0194-0

Cited by 10 publications

(10 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As yet, there is no evidence that atypical NF-κB responses are involved in additional, bortezomib-related complications. However, despite its purported anti-inflammatory effects, bortezomib treatment has been reported to induce inflammatory symptoms, such as neuropathy and increases in serum levels of pro-inflammatory cytokines [21–23]. In accordance with our findings, these symptoms suggest that proteasome inhibitors may serve to amplify rather than prevent inflammation.…”

Section: Discussionsupporting

confidence: 88%

“…For example, the proteasome inhibitor PS-341 (Velcade/bortezomib) is currently being used in the treatment of multiple myeloma, with the therapeutic benefit of bortezomib partly attributed to its ability to block NF-κB induction [19,20]. Paradoxically, many reports have described the development of inflammatory symptoms and increases in serum levels of pro-inflammatory cytokines following administration of bortezomib [21–23]. As suggested recently, complications and resistance to bortezomib treatment may stem from NF-κB signaling induced by proteasome-independent mechanisms [24].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-κB activation

Cullen

Ponnappan

2010

Biochemical Pharmacology

View full text Add to dashboard Cite

Proteasome inhibition has become synonymous with inhibition of NF-κB activity. However, hyperactive NF-κB responses often accompany physiological conditions marked by proteasomal defects, i.e. advancing age, geriatric diseases, and bortezomib resistance. These paradoxical NF-κB responses are likely to be impervious to proteasomal defects because they stem from atypical NF-κB signaling induced by upstream mechanisms which are proteasome-independent. While this atypical pathway does not require proteasome for NF-κB nuclear translocation, a role for proteasome in regulating nuclear NF-κB remains unexplored. We now demonstrate that proteasome stringently controls transcription of inflammatory mediators regulated by this atypical NF-κB pathway. Proteolytic activity of the proteasome mediates the removal of the NF-κB subunit, p65/RelA, from inflammatory genes, thereby terminating atypical NF-κB-dependent transcriptional responses. For the first time, we demonstrate that both 19S and 20S components of the 26S proteasome complex are recruited to an inflammatory gene promoter; additionally, the 19S and 20S complexes appear to play distinct roles in the negative regulation of NF-κB-dependent transcription. By demonstrating that proteasome regulates the termination of atypical NF-κB-dependent transcriptional responses, these studies clearly indicate a novel, regulatory role for proteasome in atypical NF-κB signaling. Moreover, these results signal a potential interplay between lowered proteasomal function and increased inflammation and may explain why inflammation accompanies physiological conditions under which proteasomal function is compromised, such as during advancing age or following bortezomib treatment. Given this role for proteasome in inflammation resolution, restoration of proteasome function may constitute a novel mechanism for intervening in chronic inflammatory diseases.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-κB activation

Cullen

Ponnappan

2010

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…In contrast to the DAD type, the clinical characteristics of CLS‐like and hypoxia‐type BILD may respond better to corticosteroid therapy, lowering the mortality rate in these patients. For example, some investigators report that IL‐6 and IFN‐γ production cause pyrexia, and patients with severe hypoxia display high levels of CRP, IL‐6 and TNF‐α and elevated IL‐6 mRNA expression level due to proteasome inhibition, suggesting that corticosteroid therapy would be an effective treatment for these types of BILD . Gotoh et al .…”

Section: Discussionmentioning

confidence: 99%

Bortezomib therapy‐related lung disease in Japanese patients with multiple myeloma: Incidence, mortality and clinical characterization

Yoshizawa¹,

Mukai²,

Miyazawa³

et al. 2014

Cancer Science

View full text Add to dashboard Cite

Because of the potentially high mortality rate (6.5%) associated with bortezomib-induced lung disease (BILD) in Japanese patients with relapsed or refractory multiple myeloma, we evaluated the incidence, mortality and clinical features of BILD in a Japanese population. This study was conducted under the Risk Minimization Action Plan (RMAP), which was collaboratively developed by the pharmaceutical industry and public health authority. The RMAP consisted of an intensive dissemination of risk information and a recommended countermeasure to health-care professionals. All patients treated with bortezomib were consecutively registered in the study within 1 year and monitored for emerging BILD. Of the 1010 patients registered, 45 (4.5%) developed BILD, 5 (0.50%) of whom had fatal cases. The median time to BILD onset from the first bortezomib dose was 14.5 days, and most of the patients responded well to corticosteroid therapy. A retrospective review by the Lung Injury Medical Expert Panel revealed that the types with capillary leak syndrome and hypoxia without infiltrative shadows were uniquely and frequently observed in patients with BILD compared with those with conditions associated with other molecular-targeted anticancer drugs. The incidence rate of BILD in Japan remains high compared with that reported in other countries, but the incidence and mortality rates are lower than expected before the introduction of bortezomib in Japan. This study describes the radiographic pattern and clinical characterization of BILD in the Japanese population. The RMAP seemed clinically effective in minimizing the BILD risk among our Japanese population.

show abstract

“…Similar cytokines are also proposed to be the pathogenesis behind bortezomib induced lung injury [15]. Maruyama et al [16] suggest that the origin of cytokines in bortezomib-treated patient is from bone marrow stromal cells.…”

Section: Discussionmentioning

confidence: 85%

Development of Drug-Induced Cutaneous Vasculitis in a Patient with Relapsed Angioimmunoblastic T-cell Lymphoma Treated with Novel Bortezomib and Panobinostat Combination: A Possible Surrogate Marker of Response

Lee¹,

Tan²,

Oh³

et al. 2014

CSROA

View full text Add to dashboard Cite

enlargement and cervical lymphadenopathy of 1 month duration. A lymph node biopsy done revealed the presence of a neoplastic T-lymphocytic infiltrate which stained positively for CD3, CD2 and CD7, but weakly for CD5. The association with proliferation of high endothelial venules, eosinophilia and CD21 marking the expanded but disrupted follicular dendritic cell meshwork confirmed the diagnosis AITL. A staging positron emission tomography (PET) scan and bone marrow trephine biopsy demonstrated extensive FDG avid lymphadenopathy above and below the diaphragm, and the absence of marrow involvement by lymphoma respectively. He was commenced on 21-day CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) chemotherapy for treatment of the stage IIIB AITL. He attained a PET complete response after 4 cycles of CHOP chemotherapy. The response was consolidated with 2 cycles and ICE (ifosfamide, cyclophosphamide and etoposide) regimen, followed by high dose therapy (HDT) with BEAM (carmustine, etoposide, cytarabine and melphalan) conditioning and autologous stem cell support. His response was however, short-lived and 6 months post-HDT, he had a biopsy-proven relapse with involvement of supra and infradiaphramatic lymph nodes, including the cervical and inguinal regions (Figures 1a and 2a). This was also accompanied by bone marrow disease and peripheral blood hypereosinophilia. He was subsequently enrolled into clinical trial NCT00901147 which explores the combination of bortezomib (1.3 mg/m 2 on days 1, 4, 8, 11) and panobinostat 20mg (3 times per week for 2 weeks) given in a 21-day cycle in relapsed/refractory T-cell lymphoma. Upon completion of the second cycle of the study combination, he developed scattered erythematous papular rash localised to the neck, upper trunk and forearms which were mildly pruritic (Figure 3).He did not have fever, prurisy and autoimmune manifestation. A skin biopsy performed on the lesion over his right forearm demonstrated perivascular lymphoid infiltrates with dyskeratosis of overlying epidermal keratinocytes, consistent

show abstract

Stromal cells in bone marrow play important roles in pro-inflammatory cytokine secretion causing fever following bortezomib administration in patients with multiple myeloma

Cited by 10 publications

References 16 publications

Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-κB activation

Proteasome inhibition up-regulates inflammatory gene transcription induced by an atypical pathway of NF-κB activation

Bortezomib therapy‐related lung disease in Japanese patients with multiple myeloma: Incidence, mortality and clinical characterization

Development of Drug-Induced Cutaneous Vasculitis in a Patient with Relapsed Angioimmunoblastic T-cell Lymphoma Treated with Novel Bortezomib and Panobinostat Combination: A Possible Surrogate Marker of Response

Contact Info

Product

Resources

About