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Title: Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-?B regulated gene products in multiple myeloma xenograft mouse model
Authors: Siveen, K.S 
Mustafa, N 
Li, F 
Kannaiyan, R
Ahn, K.S
Kumar, A.P 
Chng, W.-J 
Sethi, G 
Keywords: bortezomib
caspase 3
chemokine receptor CXCR4
cyclooxygenase 2
gelatinase B
immunoglobulin enhancer binding protein
interleukin 6
Ki 67 antigen
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
protein bcl 2
syndecan 1
transcription factor RelA
tumor necrosis factor alpha
antineoplastic agent
benzoquinone derivative
boronic acid derivative
immunoglobulin enhancer binding protein
pyrazine derivative
animal experiment
animal model
animal tissue
antineoplastic activity
antiproliferative activity
Bcl 2 gene
cancer cell culture
cancer inhibition
cancer resistance
cell isolation
concentration response
controlled study
cox2 gene
CXCR4 gene
drug potentiation
drug sensitivity
enzyme activation
gene disruption
gene product
human cell
IL 6 gene
in vitro study
in vivo study
ki 67 gene
migration inhibition
MMP9 gene
multiple myeloma
myeloma cell
p65 gene
protein cleavage
protein expression
TNFalpha gene
tumor invasion
tumor xenograft
VEGF gene
Bagg albino mouse
cell proliferation
disease model
drug effects
drug potentiation
drug screening
multiple myeloma
nude mouse
signal transduction
tumor cell line
Antineoplastic Combined Chemotherapy Protocols
Boronic Acids
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Drug Synergism
Mice, Inbred BALB C
Mice, Nude
Multiple Myeloma
NF-kappa B
Random Allocation
Signal Transduction
Xenograft Model Antitumor Assays
Issue Date: 2014
Publisher: Impact Journals LLC
Citation: Siveen, K.S, Mustafa, N, Li, F, Kannaiyan, R, Ahn, K.S, Kumar, A.P, Chng, W.-J, Sethi, G (2014). Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-?B regulated gene products in multiple myeloma xenograft mouse model. Oncotarget 5 (3) : 634-648. ScholarBank@NUS Repository.
Abstract: Multiple myeloma (MM) is a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow. With the advent of novel targeted agents, the median survival rate has increased to 5 -7 years. However, majority of patients with myeloma suffer relapse or develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of MM. Thus in the present study, we investigated whether thymoquinone (TQ), a bioactive constituent of black seed oil, could suppress the proliferation and induce chemosensitization in human myeloma cells and xenograft mouse model. Our results show that TQ inhibited the proliferation of MM cells irrespective of their sensitivity to doxorubicin, melphalan or bortezomib. Interestingly, TQ treatment also resulted in a significant inhibition in the proliferation of CD138+ cells isolated from MM patient samples in a concentration dependent manner. TQ also potentiated the apoptotic effects of bortezomib in various MM cell lines through the activation of caspase-3, resulting in the cleavage of PARP. TQ treatment also inhibited chemotaxis and invasion induced by CXCL12 in MM cells. Furthermore, in a xenograft mouse model, TQ potentiated the antitumor effects of bortezomib (p < 0.05, vehicle versus bortezomib + TQ; p < 0.05, bortezomib versus bortezomib + TQ), and this correlated with modulation of various markers for survival and angiogenesis, such as Ki-67, vascular endothelial growth factor (VEGF), Bcl-2 and p65 expression. Overall, our results demonstrate that TQ can enhance the anticancer activity of bortezomib in vitro and in vivo and may have a substantial potential in the treatment of MM.
Source Title: Oncotarget
ISSN: 19492553
DOI: 10.18632/oncotarget.1596
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