Boronic Acids ; Bortezomib ; Humans ; Liver Diseases ; Proteasome Inhibitors ; Pyrazines

Multiple myeloma is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells that produce monoclonal immunoglobulins. Cutaneous involvement is very uncommon in patients with multiple myeloma. It usually appears late in the course of the disease. Bortezomib is a potent proteasome inhibitor, recently introduced in the treatment of multiple myeloma. It has proven to be safe and effective in the treatment of refractory or relapsed multiple myeloma. In this study, we show the high efficacy of a concurrent therapeutic approach with bortezomib and radiation in a patient with a cutaneous plasmacytoma.
Boronic Acids ; Hematologic Neoplasms ; Humans ; Immunoglobulins ; Multiple Myeloma ; Plasma Cells ; Plasmacytoma ; Proteasome Inhibitors ; Pyrazines ; Bortezomib

The tumor lysis syndrome (TLS) commonly occurs in the lymphoproliferative disorder, either spontaneously or in response to therapy. TLS is uncommon in multiple myeloma. However, with the use of bortezomib in the treatment of multiple myeloma, cases of TLS have been reported. We report here threepatients who presented with TLS after the administration of bortezomib. Two of them presented mild symptoms and recovered with hydration only. However, death of the other patient was associated with TLS. We should monitor patients who had high tumor burden, especially in early phase of bortezomib therapy and appropriate prophylaxis for high risk patient is also needed.
Boronic Acids ; Humans ; Lymphoproliferative Disorders ; Multiple Myeloma ; Organothiophosphorus Compounds ; Pyrazines ; Tumor Burden ; Tumor Lysis Syndrome ; Bortezomib

OBJECTIVETo evaluate the efficacy and feasibility of bortezomib plus dexamethasone (BD) in patients with primary systemic (AL) amyloidosis.

METHODSEleven AL amyloidosis patients, including four relapsed or progressed after previous therapies and 7 newly diagnosed were treated with BD. Ten patients had two or more organs involved. Precursor protein analysis showed that 1 was κ light chain, 9 λ light chain; 5 patients with positive immunofixation including 1 IgG κ, 3 IgG λ and 1 IgA λ. BD was administered according to standard two-week schedule.

RESULTSEight patients were evaluable, the median number of treatment cycles was 3 (range 1 - 6). Median follow-up duration was 6 months. At least one affected organ response was observed in six patients and median time to organ response was 2 months. Three patients progressed and two of them died. Toxicities were mainly diarrhea, thrombocytopenia, peripheral neuropathy, fatigue and herpes zoster, and 7 evaluable patients who had toxicities were adjusted dosage and 2 of them interrupted therapy. Epilepsia, paralytic ileus, acute cardiac dysfunction, and postural hypotention were occurred in 3 inevaluble patients.

CONCLUSIONBortezomib plus dexamethasone is effective in AL amyloidosis. Adverse events are common, and in some patients are severe.

Amyloidosis ; drug therapy ; Boronic Acids ; therapeutic use ; Bortezomib ; Dexamethasone ; administration & dosage ; Humans ; Multiple Myeloma ; drug therapy

Boronic Acids ; adverse effects ; Bortezomib ; Humans ; Peripheral Nervous System Diseases ; chemically induced ; Pyrazines ; adverse effects

OBJECTIVETo investigate the effect of bortezomib (Bor) alone or in combination with As(2)O(3) (ATO) and/or dexamethasone (DXM) on proliferation and apoptosis in KM3 human multiple myeloma cell line KM3.

METHODSKM3 cells were cultured with different concentrations of Bor and ATO and/or DXM in combination or Bor, ATO, DXM alone for different times. Cell proliferation was assayed by MTT assay, and IC(50) was calculated. Cell morphology was observed with light and electric microscopy. The agarose gel electrophoresis was used to evaluate DNA content, and the flow cytometry was used to exam Annexin V-FITC/PI stain.

RESULTSBor, ATO and DXM inhibited KM3 cell proliferation in a time-and dose-dependent manner with the IC(50) of 0.27, 3.10 and 8.01 micromol/L, respectively. The inhibition rate of KM3 cells by Bor plus ATO and DXM was significantly higher than Bor plus ATO or DXM \[(34.51 +/- 0.51)% vs (25.39 +/- 0.90)% and (34.51 +/- 0.51)% vs (23.80 +/- 0.78)% respectively\]. Typical morphology for apoptosis and DNA ladder were observed in KM3 cell treated with 0.25 micromol/L Bor for 48 h, by Annexin V positivity. The apoptosis rate induced by Bor plus both ATO and DXM was higher than that induced by Bor plus DXM.

CONCLUSIONBor can inhibit the proliferation and induce apoptosis of KM3 cells. Bor enhances the inhibitory effect of ATO and DXM on the growth of KM3 cell. ATO enhances the apoptosis effects of Bor and DXM on KM3 cells.

Apoptosis ; drug effects ; Boronic Acids ; pharmacology ; Bortezomib ; Cell Line, Tumor ; Dexamethasone ; pharmacology ; Humans ; Multiple Myeloma ; metabolism

OBJECTIVETo investigate the effect of bortezomib (Bor) alone and in combination with arabinoside (Ara-C) on proliferation and apoptosis of leukemia cell line K562.

METHODSK562 cells were treated with 20 nmol/L Bor and 0.2 microg/ml Ara-C alone and in combination for 48 h. MTT was used to study the inhibitory effects on cell growth and the apoptosis rate was analysed by flow cytometry. After K562 cells treated with 20 nmol/L Bor or 0.2 microg/ml Ara-C for 6 h, the activity of NF-kappaB was analyzed by SP immunohistochemistry and cell cycle by flow cytometry.

RESULTSThe inhibition and apoptosis rates of K562 cells in combination groups were higher than those in the two single treatment groups (P < 0.01), especially in the combined treatment group in which K562 cells were treated first with Ara-C for 6 h then with Bor combined,the inhibition and apoptosis rates were the highest [(81.5 +/- 4.0)% and (29.2 +/- 3.1)%, respectively] (P < 0.01). In the other two combined groups in which the cells were treated with Bor for 6 h then with Ara-C combined, or treated with the two drugs simultaneously, the inhibition and apoptosis rates were (54.1 +/- 4.2)% and (18.7 +/- 3.5)%, and (66.2 +/- 2.8)% and (21.1 +/- 2.2)%, respectively. Treatment of K562 cells with 20 nmol/L Bor for 6 h, the activity of NF-kappaB was decreased significantly, and the cells were apparently arrested in G(2)/M phase, and treatment with 0.2 microg/ml Ara-C in the same manner, the activity of NF-kappaB was increased significantly, and the cells were apparently arrested in G(1) phase.

CONCLUSIONSBor can effectively inhibit K562 cell proliferation, and induced its apoptosis. This effect was enhanced significantly when in combination with Ara-C. Pretreatment of K562 cells with Ara-C lead to the increased activity of NF-kappaB and the fraction of G(1) phase cells.

Apoptosis ; drug effects ; Boronic Acids ; pharmacology ; Bortezomib ; Cell Proliferation ; drug effects ; Humans ; K562 Cells ; Pyrazines ; pharmacology

OBJECTIVETo investigate the synergistic anti-multiple myeloma (MM) effect of 2-methoxyestradiol (2-ME2) and bortezomib, and explore the relationship between this effect and blockade of aggresomes formation by 2-ME2.

METHODSFour MM cell lines RPMI-8226, NCI-H929, U266 and SKO-007 were used for study. Immunoflourescent anti-ubiquitin and Hoechst 33342 staining were used to examine aggresome-positive cells and apoptotic cells, respectively. Isobolographic analysis was used for determination of synergy.

RESULTS(1) Quantitative assay showed that in the absence of bortezomib, only 6.6% - 8.9% of MM cells were aggresome-positive, but the percentage was increased to 71.9%-83.4% after treatment with bortezomib at IC(20) concentration for 24 h. Aggresome-positive cells with immunoreactivity to anti-ubiquitin were detected in almost all non-apoptotic cells, but not in apoptotic cells. (2) Treatment in a definite range of concentrations bortezomib plus 2-ME2 led to MM cell apoptosis compared with each agent alone and the significantly synergistic effect confirmed by isobolographic analysis. (3) Combination of bortezomib and 2-ME2 increased the apoptotic cells aggresome-negative cells (ANK) and decreased the non-apoptotic cells in aggresome positive cells (APC). In RPMI8226 and U266 cells, the apoptotic cells in ANC increased from (14.5 +/- 2.0)% and (20.1 +/- 2.9)% to (80.7 +/- 6.9)% and (71.6 +/- 6.2)%, and the non-apoptotic cells in APC decreased from (75.3 +/- 5.7)% and (69.1 +/- 8.6)% to (13.8 +/- 3.8)% and (19.5 +/- 4.2)%, respectively, in combined group and bortezomib alone group.

CONCLUSIONBortezomib-induced aggresomes have a protective function for MM cells and combination of bortezomib with 2-ME2 induced a synergistic cytotoxicity to the cells.

Apoptosis ; drug effects ; Boronic Acids ; pharmacology ; Bortezomib ; Cell Line, Tumor ; Humans ; Multiple Myeloma ; metabolism ; Pyrazines ; pharmacology

Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Boronic Acids ; administration & dosage ; Bortezomib ; Humans ; Multiple Myeloma ; drug therapy ; Pyrazines ; administration & dosage

The purpose of this study was to explore the effect of proteasome inhibitor, bortezomib (Bzb), on osteoblast in pathologic status of myeloma bone disease. The myeloma bone disease was modeled by co-culture of mouse myeloma cell RPMI8226 with osteoblast line MC-3T3E1 from mouse calvaria, and intervenient culture of supernatant. The inhibitory effect of Bzb on proliferation of MC-3T3E1 assayed by modified MTT method, the apoptosis of MC-3T3E1 cells was determined by flow cytometry with Annexin V/PI staining, the expressions of osteoblast markers, Runx2/cbfa1, osteocalcin (OCN) and osterix (OSX) in MC-3T3E1 treated with Bzb were detected by RT-PCR and Western blot respectively. Experiments were divided into 3 group: single cultured, co-cultured and supernatant-interveniently cultured groups. The results showed the Bzb in higher concentration inhibited proliferation of MC-3T3E1 cells in a dose-dependent manner, with the IC(50) of 38.1 nmol/L for 48 hours, the Bzb in low concentration (5 nmol/L) did not show the inhibitory effect on proliferation of MC-3T3E1 in single cultured group (p>0.10), but could decrease apoptotic rate of MC-3T3E1 by 32.5% and 24.6% respectively in cocultured and supernatant-interveniently cultured groups, moreover increased the expression of osteoblast-related gene OSX, OCN mRNA and protein (p<0.05), while no obvious change of Runx2/cbfa1 expression was observed (p>0.05). It is concluded that the proteasome inhibitor, Bzb, in low concentration promotes the activity of osteoblast internal mechanisms, and prevents the apoptosis of osteoblasts induced by myeloma cells. In addition, it can up-regulate transcription and expression of osteoblast markers related to Runx2/cbfa1 path way, thus may protect osteoblasts in myeloma bone disease.
3T3 Cells ; Animals ; Apoptosis ; drug effects ; Boronic Acids ; pharmacology ; Bortezomib ; Cell Line, Tumor ; Mice ; Multiple Myeloma ; pathology ; Pyrazines ; pharmacology