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Treatment of Human Multiple Myeloma by Curcumin

a curcumin and multiple myeloma technology, applied in the field of cancer biology, can solve the problems of inability to treat malignancy, insufficient pharmacologically safe and effective agents, etc., and achieve the effects of suppressing constitutive ib phosphorylation, little or no toxicity, and preventing nuclear retention of p65

Inactive Publication Date: 2006-10-19
AGGARWAL BHARAT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] Because of the central role of nuclear transcription factor NF-κB in cell survival and proliferation, the possibility of using it as a target for multiple myeloma treatment was explored by using curcumin (diferuloylmethane), an agent known to have very little or no toxicity in humans. NF-κB was constitutively active in all human multiple myeloma cell lines examined and that curcumin, a chemopreventive agent, downregulated NF-κB in all cell lines as indicated by electrophoretic mobility gel shift assay and prevented nuclear retention of p65 as shown by immunocytochemistry. All multiple myeloma cell lines showed constitutively active IκB kinase (IKK) and IκBα phosphorylation. Curcumin suppressed constitutive IκBα phosphorylation through inhibition of IkB kinase activity. Curcumin also downregulated expression of NF-κB-regulated gene products including IκBα, Bcl-2, Bcl-xL, cyclin D1 and interleukin-6. This led to suppression of proliferation and arrest of cells at the G1 / S phase of the cell cycle.

Problems solved by technology

Despite treatment with large doses of glucocorticoids and alkylating agents, this malignancy remains incurable.
However, the prior art is deficient in identifying a pharmacologically safe and effective agent with which to block constitutive NF-κB in multiple myeloma.

Method used

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  • Treatment of Human Multiple Myeloma by Curcumin
  • Treatment of Human Multiple Myeloma by Curcumin
  • Treatment of Human Multiple Myeloma by Curcumin

Examples

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Effect test

example 1

Cells and Reagents

[0044] Human multiple myeloma cell lines U266, RPMI 8226, and MM.1 were obtained from the American Type Culture Collection (Rockville, Md.). Cell lines U266 (ATCC#TIB-196) and RPMI 8226 (ATCC#CCL-155) are plasmacytomas of B cell origin. U266 is known to produce monoclonal antibodies and IL-6. RPMI 8226 produces only immunoglobulin light chains and there is no evidence for heavy chain or IL-6 production. Doxorubicin (Dox-6)- and melphalan (LR-5)-resistant clones of RPMI 8226 were provided by Dr. Willium Dalton (H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.)

[0045] The MM.1 (also called MM.1S) cell line, which is established from the peripheral blood cells of a patient with IgA myeloma, secretes lambda light chain, is negative for the presence of EBV genome, and expresses leukocyte antigen DR, PCA-1, T9 and T10 antigens. MM.1R is a dexamethasone-resistant variant of MM.1 cells. These two cell lines was provided by Dr. Steve T. Rosen of Northweste...

example 2

Preparation of Nuclear Extracts for NF-κB

[0050] Nuclear extracts were prepared according to Bharti et al. (2003). Briefly, 2×106 cells were washed with cold PBS and suspended in 0.4 ml of hypotonic lysis buffer containing protease inhibitors for 30 min. The cells were then lysed with 12.5 μl of 10% Nonidet P-40. The homogenate was centrifuged, and supernatant containing the cytoplasmic extracts was stored frozen at −80° C. The nuclear pellet was resuspended in 25-μl ice-cold nuclear extraction buffer. After 30 min of intermittent mixing, the extract was centrifuged, and supernatants containing nuclear extracts were collected. Protein content was measured by the Bradford method. If the supernatants were not used immediately, they were stored at −80° C.

example 3

Electrophoretic Mobility Shift Assay for NF-κB

[0051] NF-kB activation was analyzed by electrophoretic mobility gel shift assay (EMSA) as described previously (Chaturvedi et al., 1994). In brief, 8-μg nuclear extracts prepared from curcumin-treated or untreated cells were incubated with 32P end-labeled double-stranded 45-mer of NF-kB oligonucleotide from human immunodeficiency virus-1 long terminal repeat (5′-TTGTTACAAGGGACTTTCCGCT GGGGACTTTCCAG GGAGGCGTGG-3′, SEQ ID NO. 4) for 15 min at 37° C., and the DNA-protein complex was resolved in a 6.6% native polyacrylamide gel. Radioactive bands from the dried gels were visualized and quantitated by PhosphorImager (Molecular Dynamics, Sunnyvale, Calif.) using ImageQuant software.

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Abstract

All multiple myeloma cell lines examined showed constitutively active IκB kinase (IKK), IκBα phosphorylation and constitutively active NF-κB. Curcumin, a chemopreventive agent, suppressed constitutive IκBα phosphorylation through inhibition of IKK activity and downregulated NF-κB. Curcumin also downregulated expression of NF-κB-regulated gene products such as IκBα, Bcl-2, Bcl-xL, cyclin D1 and interleukin-6. Consequently, curcumin suppressed multiple myeloma cell proliferation and arrested cells at the G1 / S phase of the cell cycle. Curcumin also induced apoptosis and chemosensitivity to vincristine. Overall, results presented herein provide a molecular basis for the treatment of multiple myeloma patients with this pharmacologically safe agent.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This non-provisional application claims benefit of provisional application U.S. Ser. No. 60 / 390,926, filed Jun. 24, 2002, now abandoned.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates generally to the field of cancer biology. More specifically, the present invention discloses methods of treating human multiple myeloma by curcumin. [0004] 2. Description of the Related Art [0005] Multiple myeloma is a B cell malignancy characterized by the latent accumulation in bone marrow of secretory plasma cells with a low proliferative index and an extended life span. Multiple myeloma accounts for 1% of all cancers and >10% of all hematologic cancers. Standard treatment regimen includes a combination of vincristine, BCNU, melphalan, cyclophosphamide, Adriamycin, and prednisone or dexamethasone. Despite treatment with large doses of glucocorticoids and alkylating agents, this malignancy remains incur...

Claims

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Application Information

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IPC IPC(8): A61K36/906A61K31/704A61K31/66A61K31/56A61K31/4745A61K31/454A61K31/12C12Q1/02A61K31/121A61K31/175A61K31/195A61K31/44A61K31/70A61K45/00A61K45/06A61P35/00A61P43/00C12Q1/48C12Q1/68
CPCA61K31/12A61K31/175A61K31/195A61K31/44A61K31/56A61K45/06A61K31/66A61K31/70A61K2300/00A61P35/00A61P43/00
Inventor AGGARWAL, BHARAT
Owner AGGARWAL BHARAT
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