Back to Search
Start Over
The pan-Bcl-2 blocker obatoclax promotes the expression of Puma, Noxa, and Bim mRNA and induces apoptosis in neoplastic mast cells.
- Source :
-
Journal of leukocyte biology [J Leukoc Biol] 2014 Jan; Vol. 95 (1), pp. 95-104. Date of Electronic Publication: 2013 Sep 19. - Publication Year :
- 2014
-
Abstract
- Advanced SM is an incurable neoplasm with short survival time. So far, no effective therapy is available for these patients. We and others have shown recently that neoplastic MC in ASM and MCL express antiapoptotic Mcl-1, Bcl-2, and Bcl-xL. In this study, we examined the effects of the pan-Bcl-2 family blocker obatoclax (GX015-070) on primary neoplastic MC, the human MC leukemia cell line HMC-1, and the canine mastocytoma cell line C2. Obatoclax was found to inhibit proliferation in primary human neoplastic MC (IC₅₀: 0.057 μM), in HMC-1.2 cells expressing KIT D816V (IC₅₀: 0.72 μM), and in HMC-1.1 cells lacking KIT D816V (IC₅₀: 0.09 μM), as well as in C2 cells (IC₅₀: 0.74 μM). The growth-inhibitory effects of obatoclax in HMC-1 cells were accompanied by an increase in expression of Puma, Noxa, and Bim mRNA, as well as by apoptosis, as evidenced by microscopy, TUNEL assay, and caspase cleavage. Viral-mediated overexpression of Mcl-1, Bcl-xL, or Bcl-2 in HMC-1 cells was found to introduce partial resistance against apoptosis-inducing effects of obatoclax. We were also able to show that obatoclax synergizes with several other antineoplastic drugs, including dasatinib, midostaurin, and bortezomib, in producing apoptosis and/or growth arrest in neoplastic MC. Together, obatoclax exerts major growth-inhibitory effects on neoplastic MC and potentiates the antineoplastic activity of other targeted drugs. Whether these drug effects can be translated to application in patients with advanced SM remains to be determined.
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Bcl-2-Like Protein 11
Cell Line, Tumor
Cell Proliferation drug effects
Drug Resistance, Neoplasm genetics
Drug Synergism
Female
Humans
Indoles
Male
Mast-Cell Sarcoma drug therapy
Mast-Cell Sarcoma mortality
Middle Aged
Myeloid Cell Leukemia Sequence 1 Protein genetics
Pyrroles therapeutic use
RNA, Messenger genetics
bcl-X Protein genetics
Apoptosis drug effects
Apoptosis Regulatory Proteins genetics
Gene Expression Regulation, Neoplastic drug effects
Mast-Cell Sarcoma genetics
Membrane Proteins genetics
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins c-bcl-2 genetics
Pyrroles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1938-3673
- Volume :
- 95
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of leukocyte biology
- Publication Type :
- Academic Journal
- Accession number :
- 24052572
- Full Text :
- https://doi.org/10.1189/jlb.1112609