The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

Khong, Tiffany; Sharkey, Janelle; Spencer, Andrew

doi:10.3324/haematol.12261

Cited by 43 publications

(30 citation statements)

References 55 publications

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“…Moreover, a phase 1/2 study . In our study, we found synergism when the orally bioavailable HSP90 inhibitor NVP-HSP990 was combined with either the DNA methyltransferase inhibitor azacytidine or the proteasome inhibitor bortezomib but the time course of anti-multiple myeloma activity when combined with the former would suggest a nonepigenetic mechanism of anti-multiple myeloma activity as we have recently described (40). The synergistic killing of the HMCL NCI H929, OCI-MY1, and U266 was not schedule dependent, however, when tested against primary multiple myeloma cells there was clear superiority when the cells were pretreated with azacytidine or bortezomib before NVP-HSP990 exposure.…”

Section: Nvp-hsp990 Induces Synergistic Cell Death Of Both Hmcl and Psupporting

confidence: 75%

Targeting HSP 90 Induces Apoptosis and Inhibits Critical Survival and Proliferation Pathways in Multiple Myeloma

Khong

Spencer

2011

Molecular Cancer Therapeutics

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The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantly older patients (>60s) and is characterized by paraprotein in the serum or urine. Clinical manifestations include anemia, hypercalcaemia, progressive renal impairment, and osteolytic bone destruction. Despite promising new therapies, multiple myeloma eventually relapses in almost all patients. HSP are ubiquitous and highly conserved in prokaryotes and eukaryote organisms. Exposure to a broad range of stimuli results in increased HSP protein expression. These chaperone proteins are involved in protein transportation, prevent protein aggregation, and ensure correct folding of nascent and stress-accumulated misfolded proteins. In cancer, HSP expression is dysregulated, resulting in elevated expression, which promotes cancer by preventing programmed cell death and supporting autonomous cells growth, ultimately leading to resistance to heat, chemotherapy, and other stresses. Client proteins of HSP90 such as AKT, p53, MEK, STAT3, and Bcr-Abl are vital in tumor progression, including multiple myeloma, and their maturation and stability is dependent on HSP90. Therefore, inhibition of HSP90 via a HSP90 inhibitor (such as NVP-HSP990) should interrupt multiple signaling pathways essential for oncogenesis and growth in multiple myeloma. Our study showed that NVP-HSP990 triggered apoptosis in a panel of human multiple myeloma cells, induced cell-cycle arrest, PARP cleavage, downregulation of client proteins, the inability to reactivate phospho-STAT3 following exogenous IL-6 stimulation, and it synergized with azacytidine and bortezomib in cell lines and primary multiple myeloma samples. The mechanism of HSP90 inhibition in multiple myeloma warrants further evaluation.

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Section: Nvp-hsp990 Induces Synergistic Cell Death Of Both Hmcl and Psupporting

confidence: 75%

Targeting HSP 90 Induces Apoptosis and Inhibits Critical Survival and Proliferation Pathways in Multiple Myeloma

Khong

Spencer

2011

Molecular Cancer Therapeutics

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“…27 Briefly, bone marrow mononuclear cells (BMMC) were isolated with Ficoll-Paque Plus (Amersham Biosciences, Rydalmere, New South Wales, Australia), washed in phosphate-buffered saline (PBS), and red blood cells were lysed with NH 4 Cl solution (8.29 g/l ammonium chloride, 0.037 g/l ethylene diamine tetraacetic acid, 1 g/l potassium bicarbonate). Cells were then washed again in PBS and quantitated by haemocytometer.…”

Section: Primary Samplesmentioning

confidence: 99%

The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells

et al. 2011

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“…Khong et al recently demonstrated that azacitidine exerts pleiotropic effects including the down‐regulation of anti‐apoptotic factors and JAK‐STAT signaling as well as the inhibition of NFκB in MM cell lines 6. In our study, the percentage of strongly p53‐positive bone marrow cells was greater than 5% at the time of the concomitant occurrence of MGUS and MDS with increase of serum IL‐6 levels; however, the levels of serum‐M protein, IL‐6 levels, the percentage of p53‐positive and CD138‐positive cells decreased after the treatment with azacitidine.…”

Section: Figurementioning

confidence: 99%

The effect of azacitidine therapy on the M protein of MDS patients with concomitant MGUS

2018

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The effect of azacitidine on interleukin-6 signaling and nuclear factor- B activation and its in vitro and in vivo activity against multiple myeloma

Cited by 43 publications

References 55 publications

Targeting HSP 90 Induces Apoptosis and Inhibits Critical Survival and Proliferation Pathways in Multiple Myeloma

Targeting HSP 90 Induces Apoptosis and Inhibits Critical Survival and Proliferation Pathways in Multiple Myeloma

The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells

The effect of azacitidine therapy on the M protein of MDS patients with concomitant MGUS

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