8-Hydrocalamenene, derived from Reynoutria elliptica, suppresses constitutive STAT3 activation, inhibiting proliferation and enhancing chemosensitization of human multiple myeloma cells
- 8-Hydrocalamenene, derived from Reynoutria elliptica, suppresses constitutive STAT3 activation, inhibiting proliferation and enhancing chemosensitization of human multiple myeloma cells
- Nam Dongwoo; Song Junho; Kim Sung-Moo; Chiang Shu Yang; Kim Ji-Sung; Chung Won-Seok; Jang Hyeung-Jin; 정상훈; Na Young-Soon; Kim Sung-Hoon; Shim Bum Sang; Ahn Kwang Seok
- Apoptosis; Chemosensitization; 8-Hydrocalamenene; Reynoutria elliptica; STAT3
- Issue Date
- Journal of medicinal food
- VOL 17, NO 3, 365-373
- 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.
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