Anti-myeloma Effects of Icariin Are Mediated Through the Attenuation of JAK/STAT3-Dependent Signaling Cascade

Abstract

Because of the essential role of signal transducer and activator of transcription 3 (STAT3) in proliferation, anti-apoptosis, and chemoresistance of multiple myeloma (MM), we investigated whether icariin, a prenylated flavonol glycoside, inhibits both constitutive and inducible STAT3 activation in human myeloma cell lines. We noted that icariin could block constitutive STAT3 phosphorylation as well as its nuclear translocation and DNA binding ability in U266 cells. Icariin also suppressed IL-6-induced STAT3 activation through the inhibition of upstream kinases (Janus activated kinase-1 and -2, and c-Src). We found that icariin downregulated the protein expression of STAT3 downstream target gene products such as Bcl-2, Bcl-xl, survivin, IAP-1/2, COX-2, VEGF, and matrix metallopeptidase 9 (MMP-9) in a concentration-dependent manner. Moreover, this flavonoid also exhibited the capacity to significantly induce apoptosis and suppress proliferation of MM cells. Interestingly, this agent also significantly potentiated the apoptotic effects of bortezomib through the suppression of STAT3 activation in MM cells. Altogether, our data indicates that the potential application of icariin as a STAT3 blocker in myeloma therapy.

RETRACTED: Optimized Icariin Phytosomes Exhibit Enhanced Cytotoxicity and Apoptosis-Inducing Activities in Ovarian Cancer Cells

“…Recently, the anti-tumor activity of ICA was reviewed [12]. It exhibited appreciable cytotoxicity against several types of cancer cells [13,14]. ICA demonstrates apoptotic effect via the intrinsic pathway [15].…”

“…ICA has poor bioavailability which can be attributed to its chemical structure. It is a diglycoside and not readily absorbed [14,21]. Its oral half-life is 3.15 h and its serum level after intravenous administration suffers rapid decline with a half-life of 0.56 h [22,23].…”

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

“…EMSA was performed to analyze the interaction of STAT3-DNA as described previously [47,48]. Briefly, cells were subjected to ACHP treatment (10 µM for 4 h) and the nuclear extract was prepared.…”

“…The protein-oligonucleotide complex was subjected to PAGE and blotted to a nylon membrane, followed by cross-linkage with UV. Lastly, the mobility of proteins was examined using a LightShift ® Chemiluminescent EMSA kit (Waltham, MA, USA) [47].…”

Attenuation of STAT3 Signaling Cascade by Daidzin Can Enhance the Apoptotic Potential of Bortezomib against Multiple Myeloma

“…We input each data point to calculate a combination index (CI) and to select a moderate combination rate. This was then used to evaluate synergy and antagonism: CI < 1, CI = 1, and CI >1, respectively [18,43,47].…”