Unknown

Dataset Information

0

Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment.


ABSTRACT: The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM.BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed.We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone. Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA (up to 3.6?±?1.2-fold induction, P?=?0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1) protein levels, which likely mediates the apoptotic effects of PTC-209. Importantly, the anti-MM activity was upheld in the presence of stromal support or myeloma growth factors insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6). In the MM microenvironment, PTC-209 impaired tube formation, impaired osteoclast development and decreased osteoblast formation in a dose-dependent manner (P?

SUBMITTER: Bolomsky A 

PROVIDER: S-EPMC4776359 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment.

Bolomsky Arnold A   Schlangen Karin K   Schreiner Wolfgang W   Zojer Niklas N   Ludwig Heinz H  

Journal of hematology & oncology 20160302


<h4>Background</h4>The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM.<h4>Methods</h4>BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publ  ...[more]

Similar Datasets

| S-EPMC6110607 | biostudies-literature
| S-EPMC5732762 | biostudies-literature
| S-EPMC7189257 | biostudies-literature
| S-EPMC4769921 | biostudies-literature
| S-EPMC9317002 | biostudies-literature
| S-EPMC5697105 | biostudies-literature
| S-EPMC6461893 | biostudies-literature
| S-EPMC4104924 | biostudies-literature
| S-EPMC3823082 | biostudies-other
| S-EPMC6943251 | biostudies-literature