Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor–κB and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis

Bharti, Alok C.; Donato, Nicholas J.; Singh, Sujay; Aggarwal, Bharat B.

doi:10.1182/blood-2002-05-1320

Cited by 650 publications

(518 citation statements)

References 53 publications

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“…We recently found that fresh BM cells obtained from MM patients express constitutively active NF-kB and STAT3 (Bharti et al, 2004). Furthermore, MM patients' myeloma cells constitutively produce IL-6 (CatlettFalcone et al, 1999;Bharti et al, 2003). Thus, it is possible that constitutively activated NF-kB induces the production of IL-6, which in turn activates STAT3 (Kaptein et al, 1996;Chatterjee et al, 2002) and MM cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…To test this hypothesis, we used U266-B1 cells, which constitutively express active NF-kB (Ni et al, 2001;Bharti et al, 2004) and produce IL-6 (Catlett-Falcone et al, 1999;Bharti et al, 2003). We incubated U266-B1 cells with Atiprimod at increasing concentrations for 4 h, and with 8 mM for 1, 4, 6, 8, and 24 h and tested the NF-kB activity in nuclear extracts.…”

Section: Atiprimod Blocks the Activation Of Nf-jbmentioning

confidence: 99%

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Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

et al. 2005

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Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod 5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a timeand dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G 0 /G 1 phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X L , and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

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Section: Discussionmentioning

confidence: 99%

Section: Atiprimod Blocks the Activation Of Nf-jbmentioning

confidence: 99%

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

et al. 2005

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“…The antiproliferative effects of diosgenin were also monitored by the thymidine incorporation method (Bharti et al, 2003).…”

Section: Thymidine Incorporation Assaymentioning

confidence: 99%

Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression

2005

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“…40, 41 Celastrol inhibited constitutively active NF-B in both of these cells ( Figure 4C-D). These results indicate a lack of cell-type specificity.…”

Section: Celastrol Inhibits Constitutive Nf-b Activationmentioning

confidence: 99%

Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation

Sethi

Ahn

Pandey

et al. 2006

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Celastrol, a quinone methide triterpene derived from the medicinal plant Tripterygium wilfordii, has been used to treat chronic inflammatory and autoimmune diseases, but its mechanism is not well understood. Therefore, we investigated the effects of celastrol on cellular responses activated by TNF, a potent proinflammatory cytokine. Celastrol potentiated the apoptosis induced by TNF and chemotherapeutic agents and inhibited invasion, both regulated by NF-B activation. We found that TNF induced the expression of gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-X L , c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP-9), and angiogenesis (VEGF) and that celastrol treatment suppressed their expression. Because these gene products are regulated by NF-B, we postulated that celastrol mediates its effects by modulating the NF-B pathway. We found that celastrol suppressed both inducible and constitutive NF-B activation. Celastrol was found to inhibit the TNF-induced activation of I B␣ kinase, I B␣ phosphorylation, I B␣ degradation, p65 nuclear trans- IntroductionModern targeted therapies for most chronic illnesses, including cancer, have been mostly unsuccessful because of their ineffectiveness, lack of safety, and cost. Although monotherapy was advocated at one time, recent experience indicates that agents that target multiple pathways have more potential in cancer treatment. This understanding has led to combination therapy. Although traditional therapies have been around for thousands of years, their active components and their mechanisms of action remain undefined. Identification of an active chemical entity and its molecular targets can lead to rediscovery of the clinical potential of such therapies, as in the case of paclitaxel, derived from Taxus (yew) species during a random screening of US Department of Agriculture collection of plants. 1 Celastrol, also known as tripterine, is one such compound that was originally identified from traditional Chinese medicine ("God of Thunder Vine") almost 3 decades ago and used for the treatment of cancer and other inflammatory diseases. 2 Celastrol, a triterpenoid from the Celastracae family and extracted from the plant Tripterygium wilfordii, 3 has attracted interest, especially for its potential anti-inflammatory effects. 4 The in vivo anti-inflammatory effects of this triterpene have been demonstrated in animal models of collagen-induced arthritis, 5 Alzheimer disease, 6 asthma, 7 systemic lupus erythematosus, 8,9 and rheumatoid arthritis. 10 Celastrol is also known to inhibit the proliferation of a variety of tumor cells, including those from leukemia, 11 gliomas, 12 and prostate cancer. 13 The ability of celastrol to modulate the expression of proinflammatory cytokines, 3,14,15 6 inducible nitric oxide (NO) synthase (iNOS), 16 adhesion molecules in endothelial cells, 17 proteasome activity, 13 topoisomerase II, 11 potassium channels, 18 and heat shock response 19 has been reported. However, the molecular mechanism underlying the ...

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Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor–κB and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis

Cited by 650 publications

References 53 publications

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression

Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation

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