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1.
Bortezomib is a novel proteasome inhibitor, which has been successfully used to treat mantle cell lymphoma and multiple myeloma. However, the direct effects of bortezomib on acute promyelocytic leukaemia (APL) have not been fully investigated. In the present study, the WST-8 assay, western blotting, flow cytometry, monodansylcadaverine staining and transmission electron microscopy were performed. It was demonstrated that bortezomib treatment induced a time- and dose-dependent decrease in the viability of NB4 cells. Bortezomib treatment induced cell apoptosis in NB4 cells, as assessed by Annexin V/propidium iodide analysis, and the detection of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, Bax and Bcl-2 expression. Furthermore, bortezomib treatment induced autophagy in NB4 cells, as indicated by autophagosome formation, p62 degradation, LC3-I to LC3-II conversion and formation of acidic autophagic vacuoles. Notably, autophagy induced by bortezomib was initiated prior to apoptosis. Inhibition of autophagy by knocking down Beclin-1 expression increased bortezomib-induced apoptosis in NB4 cells. Therefore, the present study revealed that the combination of bortezomib and autophagy inhibition may be a potential treatment strategy for APL. 相似文献
2.
Erik L. Frandsen Jessica Otero Joe C. Rutledge Mariska S. Kemna Erin L. Albers Borah J. Hong Yuk M. Law Joshua M. Friedland‐Little 《Pediatric transplantation》2020,24(1)
Bortezomib is approved for the treatment of multiple myeloma but increasingly used in heart transplant (HTx) recipients with antibody‐mediated rejection (AMR). Severe pulmonary toxicity is a rare complication in multiple myeloma patients treated with bortezomib, but has not been described in a solid organ transplant recipient. A 20‐year‐old man 7 years post‐HTx presented with acute rejection with hemodynamic compromise. Endomyocardial biopsy showed mixed rejection (ISHLT grade 2R‐3R acute cellular rejection (ACR) and pAMR 1 (I+) with diffuse C4d staining). Two new high MFI circulating MHC class‐II donor‐specific antibodies (DSA) were detected. Treatment included corticosteroids, antithymocyte globulin, plasmapheresis, IVIG, rituximab, and bortezomib (1.3 mg/m2). Due to rebound in DSA, a second course of bortezomib was started. Thrombocytopenia and peripheral neuropathy prompted a 50% dose reduction during the 2nd course. Shortly after the 3rd reduced dose, the patient developed hypoxemic respiratory failure. Bronchoscopy revealed pulmonary hemorrhage with negative infectious studies. Chest CT showed bilateral parenchymal disease with bronchiectasis and alveolar bleeding. Despite treatment with high‐dose steroids, severe ARDS ensued with multisystem organ failure. The patient expired 23 days after the final dose of bortezomib. Post‐mortem lung histology revealed diffuse alveolar damage, pulmonary fibrosis, and hemorrhage. Cardiac histology showed resolving/residual ACR 1R and pAMR 1 (I+). While rare, bortezomib‐induced lung toxicity (BILT) can occur in HTx recipients and can carry a high risk of mortality. Drug reaction and immediate drug withdrawal should be considered in patients who develop respiratory symptoms, though optimal management of BILT is unclear. 相似文献
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An open‐label phase I/II study of cyclophosphamide,bortezomib, pegylated liposomal doxorubicin,and dexamethasone in newly diagnosed myeloma 下载免费PDF全文
Taiga Nishihori Rachid Baz Kenneth Shain Jongphil Kim Jose L. Ochoa‐Bayona Binglin Yue Daniel Sullivan William Dalton Melissa Alsina 《European journal of haematology》2015,95(5):426-435
We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6–8 cycles of CVDD at four dose levels. There were no dose‐limiting toxicities. The MPD was cyclophosphamide 750 mg/m2 IV on day 1, bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m2 IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21‐d cycle). Forty‐nine patients were treated at the MPD of which 22% had high‐risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard‐risk, and 100% and 58% in high‐risk cohort, respectively. After a median follow‐up of 34 months, the median progression‐free survival was 31.3 months. The 2‐yr overall survival was 91.1% in the standard‐risk and 88.9% in the high‐risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM. 相似文献
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AMR is increasingly being recognized as an important cause of renal allograft injury, contributing to significant morbidity and graft loss. There are few controlled trials and no well‐established treatment guidelines for AMR in renal transplant recipients. We retrospectively reviewed the outcome of four pediatric renal transplant recipients on a steroid minimization immunosuppression protocol treated with bortezomib for elevated DSA and acute AMR from 2012 to 2013. All patients received four doses of bortezomib 1.3 mg/m2 given on days one, four, eight, and 11. All patients also received other treatments prior to bortezomib, which may have included rituximab, methylprednisolone, plasmapheresis, and/or IVIg. While bortezomib in addition to other therapies significantly decreased DSA titers, DSA remained very elevated months after treatment. All four patients had immediate improvement or stabilization of renal function but one eventually lost her graft. There were no adverse events related to bortezomib six months after treatment. 相似文献
7.
Eli Muchtar Angela Dispenzieri Morie A. Gertz Shaji K. Kumar Francis K. Buadi Nelson Leung Martha Q. Lacy David Dingli Sikander Ailawadhi P. Leif Bergsagel Rafael Fonseca Suzanne R. Hayman Prashant Kapoor Martha Grogan Omar F. Abou Ezzeddine Julie L. Rosenthal Michelle Mauermann Mustaqueem Siddiqui Taimur Sher 《Mayo Clinic proceedings. Mayo Clinic》2021,96(6):1546-1577
Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients’ frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti–plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti–plasma cell therapy, and supportive care. 相似文献
8.
Brijeshkumar S Patel Wai Sie Co Claudia Donat Mary Wang Wenchi Che Pavan Prabhala Friederike Schuster Vera Schulz Janet L Martin Alaina J Ammit 《Cancer biology & therapy》2015,16(5):780-789
Mitogen activated protein kinase phosphatase-1 (MKP-1) has emerged as an important protein mediating breast cancer oncogenesis and chemoresistance to cancer chemotherapies, especially proteasome inhibitors. In this in vitro study, we utilized the breast cancer epithelial cell lines MCF-7 and MDA-MB-231, in comparison to MCF-10A control cells, to examine the impact of MKP-1 on breast cancer cell growth and repression by proteasome inhibitors. We confirm that proteasome inhibitors MG-132 and bortezomib induce MKP-1 protein upregulation and we show that one of the ways in which bortezomib increases MKP-1 in breast cancer cells, in addition to inhibition of ubiquitin-proteasome system, is via upregulation of MKP-1 mRNA expression in p38 MAPK-mediated manner. Notably, these effects are specific to cancer cells, as bortezomib activated p38 MAPK and induced MKP-1 in MCF-7 and MDA-MB-231 breast cancer cells, but not in control cells (MCF-10A). We took a dual approach toward targeting MKP-1 to show that bortezomib-induced effects are enhanced. Firstly, treatment with the non-specific MKP-1 inhibitor triptolide reduces breast cancer cell growth and augments proteasome inhibitor-induced effects. Secondly, specific knock-down of MKP-1 with siRNA significantly repressed cell viability by reduced cyclin D1 expression, and enhanced repression of cancer cell growth by proteasome inhibitors. Taken together, these results indicate that removing the unwanted (MKP-1-inducing) effects of bortezomib significantly improves the efficacy of proteasome inhibition in breast cancer cells. Thus, future development of drugs targeting MKP-1 offer promise of combination therapies with reduced toxicity and enhanced cell death in breast cancer. 相似文献
9.
Jagannath S Barlogie B Berenson JR Siegel DS Irwin D Richardson PG Niesvizky R Alexanian R Limentani SA Alsina M Esseltine DL Anderson KC 《British journal of haematology》2008,143(4):537-540
The Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST) demonstrated substantial activity with two dose levels of bortezomib (1.0 and 1.3 mg/m(2)), alone or with dexamethasone, in relapsed or refractory multiple myeloma. We present updated survival analyses after prolonged follow-up (median >5 years). One- and 5-year survival rates were 82% and 32%, respectively, in the 1.0 mg/m(2) group (n = 28), and 81% and 45%, respectively, in the 1.3 mg/m(2) group (n = 26). Notable survival, response, and time-to-progression data suggest that a bortezomib starting dose of 1.3 mg/m(2) is preferred. If bortezomib dose reduction is required, the 1.0 mg/m(2) dose still offers patients a substantial survival benefit. 相似文献
10.
Kevin R. Kelly Claudia M. Espitia Weiguo Zhao Erik Wendlandt Guido Tricot Fenghuang Zhan Jennifer S. Carew Steffan T. Nawrocki 《Oncotarget》2015,6(38):41275-41289
Despite the development of several new agents for multiple myeloma (MM) therapy over the last decade, drug resistance continues to be a significant problem. Patients with relapsed/refractory disease have high mortality rates and desperately need new precision approaches that directly target specific molecular features that are prevalent in the refractory setting. Reolysin is a proprietary formulation of reovirus for cancer therapy that has demonstrated efficacy in multiple clinical trials. Its selective effects against solid tumors have been largely attributed to RAS-mediated control of reovirus replication. However, the mechanisms regulating its preferential anti-neoplastic effects in MM and other hematological malignancies have not been rigorously studied. Here we report that the reovirus receptor, junctional adhesion molecule-A (JAM-A) is highly expressed in primary cells from patients with MM and the majority of MM cell lines compared to normal controls. A series of experiments demonstrated that JAM-A expression, rather than RAS, was required for Reolysin-induced cell death in MM models. Notably, analysis of paired primary MM specimens revealed that JAM-A expression was significantly increased at relapse compared to diagnosis. Two different models of acquired resistance to bortezomib also displayed both higher JAM-A expression and elevated sensitivity to Reolysin compared to parental cells, suggesting that Reolysin may be an effective agent for patients with relapsed/refractory disease due to their high JAM-A levels. Taken together, these findings support further investigation of Reolysin for the treatment of patients with relapsed/refractory MM and of JAM-A as a predictive biomarker for sensitivity to Reolysin-induced cell death. 相似文献