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Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model
- Source :
- Oncotarget, Scopus-Elsevier
- Publication Year :
- 2013
- Publisher :
- Impact Journals LLC, 2013.
-
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.
- Subjects :
- Male
Angiogenesis
Mice, Nude
Apoptosis
Pharmacology
NF-κB
Bortezomib
chemistry.chemical_compound
Mice
Random Allocation
immune system diseases
hemic and lymphatic diseases
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
Benzoquinones
Medicine
Animals
Humans
Doxorubicin
Thymoquinone
Multiple myeloma
Cell Proliferation
Mice, Inbred BALB C
business.industry
Cell growth
NF-kappa B
Drug Synergism
medicine.disease
MM
Boronic Acids
Xenograft Model Antitumor Assays
Disease Models, Animal
medicine.anatomical_structure
Oncology
chemistry
Pyrazines
Bone marrow
business
Multiple Myeloma
medicine.drug
Research Paper
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 5
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....0937c58d07539060c643ffe40ed5b805