The pan-Bcl-2 blocker obatoclax promotes the expression of Puma, Noxa, and Bim mRNA and induces apoptosis in neoplastic mast cells.
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.
1.Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, A-1090 Vienna, Austria. peter.valent@meduniwien.ac.at.
Barbara
B
Peter
Sabine
S
Cerny-Reiterer
Emir
E
Hadzijusufovic
Karina
K
Schuch
Gabriele
G
Stefanzl
Gregor
G
Eisenwort
Karoline V
KV
Gleixner
Gregor
G
Hoermann
Matthias
M
Mayerhofer
Michael
M
Kundi
Sigrid
S
Baumgartner
Wolfgang R
WR
Sperr
Winfried F
WF
Pickl
Michael
M
Willmann
Peter
P
Valent
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D008297:Male; D012515:Mast-Cell Sarcoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007211:Indoles; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D012333:RNA, Messenger; D051020:bcl-X Protein; C520962:obatoclax
Mcl-1; mastocytosis; targeted therapy