Decursin chemosensitizes human multiple myeloma cells through inhibition of STAT3 signaling pathway.
Recent reports have indicated that decursin can induce apoptosis, suppress tumor growth, and inhibit angiogenesis. In this experiment, we investigated how decursin could potentiate the cytotoxic effects of bortezomib in human multiple myeloma cells. We found that decursin inhibited cell viability in U266, MM.1S and ARH77 cells, but not in peripheral blood mononuclear cells (PBMC). Decursin-induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. This correlated with the down-regulating of cyclin D1, bcl-2, bcl-xL, survivin, and the vascular endothelial growth factor (VEGF), which are all regulated by the activation of signal transducers and the activator of transcription 3 (STAT3). Indeed, decursin inhibited constitutive STAT3 activation through inhibition of the activation of Janus-activated kinase 2 (JAK2) in U266 cells. In addition, decursin inhibited interleukin-6-inducible STAT3 activation in a time-dependent manner in MM.1S cells. Interestingly, decursin significantly potentiated the apoptotic effects of bortezomib in U266 cells. These effects of decursin were correlated with the suppression of constitutive STAT3 activation in U266 cells. Overall, these results suggest that decursin is a novel blocker of STAT3 activation and it may be a potential candidate for overcoming chemo-resistance through suppression of this signaling.
Department of Oriental Pathology, College of Oriental Medicine and Institute of Oriental Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Republic of Korea.
Hyun Jung
HJ
Kim
Sung-Moo
SM
Kim
Kyung-Ran
KR
Park
Hyeung-Jin
HJ
Jang
Young-Soon
YS
Na
Kyoo Seok
KS
Ahn
Sung-Hoon
SH
Kim
Kwang Seok
KS
Ahn
D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002087:Butyrates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000032:analysis; D004247:DNA / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D011719:Pyrazines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D001578:Benzopyrans; D001897:Boronic Acids; D002087:Butyrates; C530105:Ccnd1 protein, mouse; D015850:Interleukin-6; D011719:Pyrazines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019938:Cyclin D1; D000069286:Bortezomib; D004247:DNA; C101278:decursin; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D053148:Caspase 3