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

Young Yun Jung,Ojas A Namjoshi,Jae-Young Um,Dongwoo Nam,Jong Hyun Lee,Bruce E Blough,Kwang Seok Ahn,Acharan S Narula,Gautam Sethi

doi:10.3389/fphar.2018.00531

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.

Highlights

Epimedium, commonly called horny goat weed in the West that is known as Yin Yang Huo in Chinese medicine, is commonly used as a tonic, aphrodisiac, anti-rheumatic and anti-cancer agent in traditional herbal remedies in China, other parts of Asia (Liu et al, 2006; Li C. et al, 2015; Tan et al, 2016)
Multiple myeloma is a malignant cancer of the plasma cells characterized by cytogenetic abnormalities and is a feature in patients with monoclonal gammopathy of uncertain significance (MGUS), the first stage that may progress to myeloma (Anderson, 2011a, b; Abdi et al, 2013)
MM cells are more often found adhered to stromal cells that secrete IL-6 and the secreted cytokine acts in a paracrine fashion and drives MM cells to proliferate at a faster pace by activating the prosurvival JAK/STAT signaling pathway (Kannaiyan et al, 2011, 2012; Sikka et al, 2014; Chai et al, 2015)

Summary

Introduction

Epimedium (family Berberidaceae), commonly called horny goat weed in the West that is known as Yin Yang Huo in Chinese medicine, is commonly used as a tonic, aphrodisiac, anti-rheumatic and anti-cancer agent in traditional herbal remedies in China, other parts of Asia (Liu et al, 2006; Li C. et al, 2015; Tan et al, 2016). In a number of recent studies, icariin has shown potent anti-tumor activity in very broad classes of cancer cell types such as gastric (Wang et al, 2010), liver (Li S. et al, 2010; Li et al, 2014), gallbladder (Zhang et al, 2013), colon (Zhang et al, 2014), breast (Ma et al, 2014), ovarian (Li J. et al, 2015), and esophageal cancer cells (Fan et al, 2016; Gu et al, 2017) These results suggest that icariin is a promising lead compound with high efficiency in cancer prevention and treatment as reported with various other agents derived from natural sources (Shanmugam et al, 2011; Tang et al, 2014; Bishayee and Sethi, 2016). Despite significant advances in scientific understanding and clinical management of MM, it remains a nearly uniformly fatal disease, with the currently available therapeutic strategies producing a mean 5-year survival rate of 49% based on MM. (Statistics obtained from www.cancer.net)

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