New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma.
OBJECTIVE
Propranolol, a non-selective β-adrenergic receptor blocker, has been used for the treatment of the patients with hypertension for more than 50 years. There are several in vitro and in vivo evidences that β-adrenergic receptor antagonists inhibit proliferation and angiogenesis and also increase apoptosis in breast, skin, and colon cancers. The aim of this study was to investigate the cytotoxic and apoptotic effects of propranolol and the genes involved in propranolol-induced apoptosis in multiple myeloma cells.


METHODS
Time-dependent antiproliferation and apoptotic effects of propranolol were subsequently determined by MTT cell proliferation assay, changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP), and also the localization of phosphatidylserine in the plasma membrane. Changes in expression levels of NF-ΚB pathway were examined by qRT-PCR array.


RESULTS
IC50 values of propranolol on U266 cells were calculated as 141, 100, and 75 μM after 24-, 48-, and 72-h propranolol exposure, respectively. There were significant increases in caspase-3 activity, loss of MMP, and increases in apoptotic cell population in response to propranolol in U266 cells in a time- and dose-dependent manner. There were increases in expression levels of BCL10, TRAF family members, interleukins, TLR1-4, TNFRSF10B, NF-κB, and the inhibitors of NF-κB genes, and significant decreases in expression levels of Bcl-2 in response to propranolol treatment were observed.


CONCLUSIONS
These results revealed that propranolol has antiproliferative and apoptotic effects on multiple myeloma cells. Being supported with in vivo analyses, propranolol can be a good and economical way to treat multiple myeloma patients.
Adana Adult Bone Marrow Center, Cell Processing Unit, Baskent University, Ankara, Turkey.
Ilknur
I
Kozanoglu
Melis Kartal
MK
Yandim
Zeynep Birsu
ZB
Cincin
Hakan
H
Ozdogu
Bedia
B
Cakmakoglu
Yusuf
Y
Baran
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D000970:Antineoplastic Agents; D016328:NF-kappa B; D011433:Propranolol; D053148:Caspase 3