Pterostilbene Inhibits Human Multiple Myeloma Cells via ERK1/2 and JNK Pathway In Vitro and In Vivo

Abstract As multiple myeloma tumors universally dysregulate cyclin D genes we conducted high-throughput chemical library screens for compounds that induce suppression of cyclin D2 promoter transcription. The top-ranked compound was a natural triterpenoid, pristimerin. Strikingly, the early transcriptional response of cells treated with pristimerin closely resembles cellular responses elicited by proteosome inhibitors, with rapid induction of heat shock proteins, activating transcription factor 3 (ATF3), and CHOP. Enzymatic assays and immunoblotting confirm that pristimerin rapidly (< 90 minutes) and specifically inhibits chymotrypsin-like proteosome activity at low concentrations (< 100 nM) and causes accumulation of cellular ubiquitinated proteins. Notably, cytotoxic triterpenoids including pristimerin inhibit NF-κB activation via inhibition of IKKα or IKKβ, whereas proteosome inhibitors instead suppress NF-κB function by impairing degradation of ubiquitinated IκB. By inhibiting both IKK and the proteosome, pristimerin causes overt suppression of constitutive NF-κB activity in myeloma cells that may mediate its suppression of cyclin D. Multiple myeloma is exquisitely sensitive to proteosome or NF-κB pathway inhibition. Consistent with this, pristimerin is potently and selectively lethal to primary myeloma cells (IC50 < 100 nM), inhibits xenografted plasmacytoma tumors in mice, and is synergistically cytotoxic with bortezomib—providing the rationale for pharmaceutical development of triterpenoid dual-function proteosome/NF-κB inhibitors as therapeutics for human multiple myeloma and related malignancies.

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Cucurbitacin B exerts anti-cancer activities in human multiple myeloma cells in vitro and in vivo by modulating multiple cellular pathways

Oncotarget ◽

10.18632/oncotarget.10584 ◽

2016 ◽

Vol 8 (4) ◽

pp. 5800-5813 ◽

Cited By ~ 12

Author(s):

Tai Yang ◽

Jin Liu ◽

Mali Yang ◽

Ning Huang ◽

Yueling Zhong ◽

...

Keyword(s):

Multiple Myeloma ◽

Myeloma Cells ◽

Cucurbitacin B ◽

Anti Cancer ◽

Human Multiple Myeloma ◽

Cellular Pathways

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Effects of short-hairpin RNA-inhibited β-catenin expression on the growth of human multiple myeloma cells in vitro and in vivo

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.05.054 ◽

2012 ◽

Vol 422 (4) ◽

pp. 681-686 ◽

Cited By ~ 4

Author(s):

Wenqing Liang ◽

Chengwei Yang ◽

Yu Qian ◽

Qiang Fu

Keyword(s):

Multiple Myeloma ◽

Short Hairpin Rna ◽

Hairpin Rna ◽

Myeloma Cells ◽

Human Multiple Myeloma ◽

Short Hairpin

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Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽

10.1038/s41388-020-01590-8 ◽

2021 ◽

Author(s):

Yinyin Xu ◽

Jing Guo ◽

Jing Liu ◽

Ying Xie ◽

Xin Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Combined Treatment ◽

Hypoxia Inducible Factor ◽

Bone Destruction ◽

Bone Lesions ◽

Myeloma Cells ◽

Downstream Target ◽

Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple myeloma [see comments]

Blood ◽

10.1182/blood.v84.9.3017.3017 ◽

1994 ◽

Vol 84 (9) ◽

pp. 3017-3025 ◽

Cited By ~ 52

Author(s):

VS Goldmacher ◽

LA Bourret ◽

BA Levine ◽

RA Rasmussen ◽

M Pourshadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Tumor Cell Line ◽

Covalent Attachment ◽

Myeloma Cells ◽

Colony Forming Units

Abstract We report the development of a potent anti-CD38 immunotoxin capable of killing human myeloma and lymphoma cell lines. The immunotoxin is composed of an anti-CD38 antibody HB7 conjugated to a chemically modified ricin molecule wherein the binding sites of the B chain have been blocked by covalent attachment of affinity ligands (blocked ricin). Conjugation of blocked ricin to the HB7 antibody has minimal effect on the apparent affinity of the antibody and no effect on the ribosome-inactivating activity of the ricin A-chain moiety. Four to six logs of CD38+ tumor cell line kill was achieved at concentrations of HB7-blocked ricin in the range of 0.1 to 3 nmol/L. Low level of toxicity for normal bone marrow (BM) granulocyte-macrophage colony- forming units (CFU-GM), burst-forming units-erythroid (BFU-E), colony- forming units-granulocyte/erythroid/monocyte/macrophage (CFU-GEMM) cells was observed. Greater than two logs of CD38+ multiple myeloma cells were depleted from a 10-fold excess of normal BM mononuclear cells (BMMCs) after an exposure to HB7-blocked ricin under conditions (0.3 nmol/L) that were not very toxic for the normal BM precursors. HB7- blocked ricin was tested for its ability to inhibit protein synthesis in fresh patients' multiple myeloma cells and in normal BMMCs isolated from two healthy volunteers; tumor cells from four of five patients were 100-fold to 500-fold more sensitive to the inhibitory effect of HB7-blocked ricin than the normal BM cells. HB7 antibody does not activate normal resting peripheral blood lymphocytes, and HB7-blocked ricin is not cytotoxic toward these cells at concentrations of up to 1 nmol/L. The potent killing of antigen-bearing tumor cells coupled with a lack of effects on peripheral blood T cells or on hematopoietic progenitor cells suggests that HB7-blocked ricin may have clinical utility for the in vivo or in vitro purging of human multiple myeloma cells.

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Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma

Blood ◽

10.1182/blood-2014-03-559385 ◽

2014 ◽

Vol 124 (12) ◽

pp. 1915-1925 ◽

Cited By ~ 44

Author(s):

Jagadish Kummetha Venkata ◽

Ningfei An ◽

Robert Stuart ◽

Luciano J. Costa ◽

Houjian Cai ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Survival ◽

Specific Inhibitor ◽

Sphingosine Kinase ◽

Myeloma Cell ◽

Myeloma Cells ◽

Sphingosine Kinase 2 ◽

Key Points

Key Points SK2 is overexpressed in myeloma cells and contributes to myeloma cell survival and proliferation. SK2-specific inhibitor promotes proteasome degradation of Mcl-1 and c-Myc and inhibits myeloma growth in vitro and in vivo.

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Abstract 1569: Antitumor activity of SR16388 against human multiple myeloma in vitro and in vivo

10.1158/1538-7445.am10-1569 ◽

2010 ◽

Author(s):

Wan-Ru Chao ◽

Yihui Shi ◽

Dominic Dinh ◽

Carol Hou ◽

Lidia Sambucetti

Keyword(s):

Multiple Myeloma ◽

Antitumor Activity ◽

Human Multiple Myeloma

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Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma

Blood ◽

10.1182/blood.v74.1.11.11 ◽

1989 ◽

Vol 74 (1) ◽

pp. 11-13 ◽

Cited By ~ 182

Author(s):

XG Zhang ◽

B Klein ◽

R Bataille

Keyword(s):

Multiple Myeloma ◽

Growth Factor ◽

Cell Growth ◽

Interleukin 6 ◽

Myeloma Cell ◽

S Phase ◽

Myeloma Cells ◽

Severity Of The Disease

Abstract It has recently been demonstrated that interleukin-6 (IL-6) is a potent myeloma-cell growth factor in the majority of patients with multiple myeloma (MM). Using an anti-bromodeoxyuridine monoclonal antibody (MoAb) to specifically count myeloma cells in the S-phase (ie, labeling index, LI), we demonstrate that the IL-6 responsiveness of myeloma cells in vitro is directly correlated with their LI in vivo. Myeloma cells from all 13 patients with high LIs in vivo (greater than or equal to 1%) responded in vitro to IL-6, the strongest response occurring in cells from five patients with plasma-cell leukemia. In contrast, the cells of only two of eight patients with low myeloma-cell LIs in vivo (less than 1%) responded to IL-6 in vitro. After seven days of culturing with 1,000 U/mL recombinant IL-6 (rIL-6), the median LI value in the first group of patients (in vivo LI greater than or equal to 1%) was 11%, ie 11 times higher (P less than .01) than the median LI value (1%) in the second group of patients (in vivo LI less than 1%). Thus, the in vitro IL-6 responsiveness of myeloma cells is directly related to their in vivo proliferative status, and hence to the severity of the disease.

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