8-hydrocalamenene, derived from Reynoutria elliptica, suppresses constitutive STAT3 activation, inhibiting proliferation and enhancing chemosensitization of human multiple myeloma cells.
The identification of the active compounds of herbal medicines and the molecular targets of those compounds is an attractive therapeutic objective. Reynoutria elliptica has been used for the treatment of various inflammatory diseases as a Korean folk remedy. Based on the evidence that anti-inflammatory agents frequently exert antiproliferative activity, we tested two sesquiterpene derivatives, 8-hydrocalamenene (HC) and 8,14-dihydrocalamenene (DHC), for their ability to induce apoptosis and suppress signal transducer and activator of transcription 3 (STAT3) activation in multiple myeloma (MM) U266 cells. We found that HC inhibited cell viability in U266, but not in peripheral blood mononuclear cells. HC exerted significant cytotoxicity and induced substantial subG1-phase arrest and apoptosis as compared with DHC. HC inhibited the expression of gene products involved in antiapoptosis (Bcl-2 and Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9), all of which are known to be regulated by STAT3. Furthermore, HC up-regulated cyclin-dependent kinase inhibitor p21 and induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. Interestingly, HC blocked constitutive STAT3 activation through the inhibition of activation of upstream kinases Janus-like kinase 1 (JAK1), JAK2, and c-Src and up-regulated PIAS3. Deletion of STAT3 reversed cytotoxic effects and the down-regulation of cyclin D1 and c-myc by HC in MM cells. Finally, this sesquiterpene significantly synergized the cytotoxic and apoptotic effects of bortezomib in U266 cells. Taken together, these results suggest that HC is a novel blocker of STAT3 activation which may have a potential in the prevention and treatment of MM.
1 College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University , Seoul, Republic of Korea.
Dongwoo
D
Nam
Junho
J
Song
Sung-Moo
SM
Kim
Shu Yuan
SY
Chiang
Ji-Sung
JS
Kim
Won-Seok
WS
Chung
Hyeung-Jin
HJ
Jang
Sang Hoon
SH
Jung
Young-Soon
YS
Na
Sung-Hoon
SH
Kim
Bum Sang
BS
Shim
Kwang Seok
KS
Ahn
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010936:Plant Extracts / Q000494:pharmacology*; D000081223:Polycyclic Sesquiterpenes; D028502:Polygonum / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D000081223:Polycyclic Sesquiterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D013729:Terpenes; C502644:calamenene; D019938:Cyclin D1; D053614:Janus Kinase 2; D053181:Caspase 8