OBJECTIVETo investigate the reverse effect of mutidrug resistance of curcumin combined with melphalan on the mutidrug-resistant human multiple myeloma cell line MOLP-2/R and the relation with FA/BRCA pathway.

METHODSThe inhibitory effects of the drugs on the growth of MOLP-2/R cells were determined by MTT assay. Cell cycle analysis, intracellular drug concentration and apoptosis were assayed by flow cytometry. The expression of FANCD2 monoubiquitination was determined by Western blot analysis.

RESULTSCo-administration of curcumin and melphalan had an synergistic inhibitory effects on the proliferation, IC50 of melphalan with 10 micromol/L curcumin reduced from 45.5 micromol/L to 19 micromol/L in MOLP-2/R cells. The apoptosis percentage of MOLP-2/R cells was significantly increased from (23.3 +/- 0.6)% to (52.6% +/- 0.8)% by the treatment of melphalan 20 micromol/L plus curcumin 10 micromol/L with the increased percentage of cells in the G2/M phase (from 9.1% to 18.5%) and enhanced intracellular drug concentration of MOLP-2/ R cells (from 15.2 +/- 0.3 to 21.4 +/- 0.8 ). The effects were accompanied with inhibition of FA/BRCA pathway by down regulation of FANCD2 protein monoubiquitination.

CONCLUSIONCurcumin combined with melphalan results in synergistic effects and reverses multiple drug resistance of MOLP-2/R cells effectively. The inhibition of FA/BRCA pathway may be the mechanism.

Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Curcumin ; pharmacology ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; drug effects ; Fanconi Anemia Complementation Group D2 Protein ; metabolism ; Humans ; Multiple Myeloma ; drug therapy ; metabolism ; pathology

The purpose of this study was to investigate the effect of bisphosphonate combined with chemotherapy on bone mineral density (BMD) of patients with multiple myeloma (MM) and analyse its value of BMD detection in clinic of these patients. 53 MM cases were enrolled in this study, including 33 newly diagnosed, 10 refractory/relapsed and 10 stable cases. They were divided randomly into two groups, 33 MM cases were treated with bisphosphonates combined with chemotherapy and 20 MM cases were treated with chemotherapy alone. The chemotherapy schedules for all patients were same. BMD was tested using the dual energy X-ray absorptiometry at 2 time points, i.e. pretreatment (basal level) and 12 months after treatment with chemotherapy and bisphosphonates. Comparisons was performed with t tests using SPSS 11.0 software. The results indicated that there was minor difference between 2 groups for BMD scores of whole body and lumbar vertebra (L1-L4), but no difference for scores of the near-end of left femur. After treatment for 12 months, all BMD scores (whole body, lumbar vertebra and the near-end of left femur) increased significantly in the bisphosphonate combined with chemotherapy group (P < 0.05). In contrast, only minor changes were seen in chemotherapy alone group. It is concluded that the bisphosphonate combined with chemotherapy has displayed promotive effect on BMD of MM patients, the detection of BMD is sensitive and special method for monitoring therapeutic effect of bisphosphonate in MM patients, thus has useful value in clinic of these patients.
Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Bone Density ; drug effects ; Diphosphonates ; administration & dosage ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Multiple Myeloma ; drug therapy ; metabolism ; pathology

A new staging system for multiple myeloma (MM) has utilized serum concentrations of beta 2-microglobulin (S beta2 M) and albumin as important prognostic factors for survival. Since S beta2 M is an indicator of glomerular filtration rate, we compared the prognostic values of S beta2 M and 24-hr urinary creatinine clearance (Ccr) in patients with MM. We retrospectively reviewed the records of 170 MM patients from January 1996 to November 2003 whose 24-hr urinary Ccr was available at the time of diagnosis. We found that pretreatment S beta2 M was inversely related to Ccr (Spearman's correlation coefficient=-0.787). In univariate analysis, the hazard ratio (HR) of death was 1.043 (p<0.001) for S beta2 M and 0.985 (p<0.001) for Ccr. Multivariate analysis showed that S beta2 M (HR 1.030, p=0.010) and Ccr (HR 0.993, p=0.059) were significant prognostic factors in patients' survival. In conclusion, 24-hr urinary Ccr may be utilized for staging of patients with MM.
beta 2-Microglobulin/*blood ; Survival Analysis ; Retrospective Studies ; Prognosis ; Neoplasm Staging/methods ; Multivariate Analysis ; Multiple Myeloma/drug therapy/metabolism/*pathology ; Creatinine/*urine

This study was aimed to further explore whether brain derived neurotrophic factor (BDNF) pathway is a potential therapeutic target in multiple myeloma (MM) and whether anti-BDNF monoclonal antibody can prevent the development of this disease. The in vivo antitumor effect of anti-BDNF monoclonal antibody (McAb) on a human myeloma xenograft animal model was evaluated. The model of xenograft tumors was established in the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice by subcutaneous injection of human myeloma cell line RPMI8226. The antibodies were injected intraperitoneally at a dose of 20 microg/mouse at day 1, 2, 3 after inoculation or at a dose of 100 microg/mouse once a week after tumors were detected. The microvascular densities in tumors were analyzed by immunohistochemistry study. The effect of anti-BDNF McAb on the proliferation of RPMI8226 cells in vitro and on endothelial cells network formation in the co-culture system were determined by using a (3)H-thymidine incorporation assay and a Matrigel network formation assay, respectively. The results showed that multiple injections of anti-BDNF McAb reduced the tumor size, decreased the microvascular density and significantly prolonged tumor-free time and survival time. Moreover, the proliferation of RPMI8226 cells was inhibited in vitro by anti-BDNF McAb, but not by the control IgG. Anti-BDNF McAb also inhibited RPMI8226-induced network formation in endothelial cells in vitro. It is concluded that anti-BDNF monoclonal antibody can inhibit cell growth and angiogenesis in subcutaneous plasmacytoma.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Brain-Derived Neurotrophic Factor ; immunology ; Cell Line, Tumor ; Humans ; Male ; Mice ; Mice, SCID ; Multiple Myeloma ; drug therapy ; metabolism ; pathology ; Neoplasms, Plasma Cell ; drug therapy ; Xenograft Model Antitumor Assays

OBJECTIVETo investigate the expression of B7 co-stimulatory molecules in human multiple myeloma (MM) and the immunoregulatory effects of thalidomide on B7.1 co-stimulator.

METHODSThe immunoregulatory effects of thalidomide on the expression of B7-1 in human MM cell line was examined by detecting the changes in the expression of B7 co-stimulator on the cells using flow cytometry following the drug treatment.

RESULTSThe expression of B7.1 co-stimulator was lowly expressed in human MM cell line and MM patients, with a positivity rate of 0.8 and (2.19-/+2.13) for B7.1 and a rate of 26.4 and (30.28-/+28.11) for B7.2, respectively. Compared with the control group, the thalidomide-treated cells showed significantly increased percentage of CD-80 positive cells in a dose-dependent manner (but not at 0.1 microg/ml) (P<0.01), with the highest percentage reaching (17.7-/+1.53)% at thalidomide concentration of 5 microg/ml.

CONCLUSIONMM cells express low or undetectable levels of B7.1. Thalidomide can up-regulate the expression of B7-1 molecules on myeloma cells, which is probably one of the therapeutic mechanisms of thalidomide.

Adult ; Aged ; Aged, 80 and over ; B7-1 Antigen ; drug effects ; metabolism ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Multiple Myeloma ; drug therapy ; immunology ; pathology ; Thalidomide ; therapeutic use ; Up-Regulation ; drug effects

To explore the effects of arsenic trioxide on multiple myeloma (MM) cell line KM(3) and its possible mechanism, cell viability was counted by trypan-blue exclusion, apoptosis was detected by morphology and DNA ladder; cell cycle was assayed by flow cytometry (FCM), telomerase activity was determined by semi-quantitative telomeric repeat amplification protocol (TRAP)-reverse transcription polymerase chain reaction (RT-PCR)-enzyme linked immunosorbent assay (ELISA), while the expression of hTERT mRNA in transcriptional level was measured by using RT-PCR. The results showed that arsenic trioxide inhibited the growth and viability of KM(3) cell and induced apoptosis; cell cycle was arrested in G(2) phase; arsenic trioxide could inhibit telomerase activity, which consisted with the downtrend of hTERT mRNA expression. In conclusion, down-regulation of telomerase activity and hTERT may play an important role in the apoptosis of MM cell line KM(3) induced by arsenic trioxide.
Antineoplastic Agents ; pharmacology ; Arsenicals ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; DNA-Binding Proteins ; Humans ; Multiple Myeloma ; drug therapy ; enzymology ; pathology ; Oxides ; pharmacology ; RNA, Messenger ; analysis ; Telomerase ; genetics ; metabolism

ADP-ribosyl Cyclase 1 ; metabolism ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Biomarkers, Tumor ; metabolism ; Biopsy ; Bone Neoplasms ; drug therapy ; metabolism ; pathology ; CD56 Antigen ; metabolism ; Humans ; Ilium ; Interferon Regulatory Factors ; Male ; Middle Aged ; Multiple Myeloma ; drug therapy ; metabolism ; pathology ; Syndecan-1 ; metabolism

Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor-kappaB (NF-κB) p65, pp65, pIKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, pIKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF-κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.
Antineoplastic Agents ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Bortezomib ; pharmacology ; therapeutic use ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; drug effects ; Drug Screening Assays, Antitumor ; Humans ; Multiple Myeloma ; drug therapy ; metabolism ; pathology ; NF-kappa B ; metabolism ; Signal Transduction ; drug effects ; Structure-Activity Relationship ; Ubiquitin-Protein Ligases ; genetics ; metabolism

Antineoplastic Agents ; pharmacology ; Arsenicals ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Membrane ; drug effects ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Humans ; Multiple Myeloma ; drug therapy ; metabolism ; pathology ; Oxides ; pharmacology ; Potassium Channel Blockers ; pharmacology ; Potassium Channels, Voltage-Gated ; drug effects

We report a rare case of multiple myeloma with biclonal gammopathy (IgG kappa and IgA lambda type) in a 58-year-old man with prostate cancer who presented with lower back pain. Through computed tomography (CT) imaging, an osteolytic lesion at the L3 vertebra and an enhancing lesion of the prostate gland with multiple lymphadenopathies were found. In the whole body positron emission tomography-computed tomography (PET-CT), an additional osteoblastic bone lesion was found in the left ischial bone. A prostate biopsy was performed, and adenocarcinoma was confirmed. Decompression surgery of the L3 vertebra was conducted, and the pathologic result indicated that the lesion was a plasma cell neoplasm. Immunofixation electrophoresis showed the presence of biclonal gammopathy (IgG kappa and IgA lambda). Bone marrow plasma cells (CD138 positive cells) comprised 7.2% of nucleated cells and showed kappa positivity. We started radiation therapy for the L3 vertebra lesion, with a total dose of 3,940 cGy, and androgen deprivation therapy as treatment for the prostate cancer.
Adenocarcinoma/complications/*diagnosis/radiotherapy ; Antineoplastic Agents/therapeutic use ; Bone Marrow Cells/metabolism/pathology ; Combined Modality Therapy ; Humans ; Immunoelectrophoresis ; Immunoglobulin kappa-Chains/blood ; Immunoglobulin lambda-Chains/blood ; Male ; Middle Aged ; Multiple Myeloma/complications/*diagnosis/drug therapy ; Neoplasm Staging ; Positron-Emission Tomography ; Prostatic Neoplasms/complications/*diagnosis/radiotherapy ; Spine/pathology ; Syndecan-1/metabolism ; Tomography, X-Ray Computed