Icaritin Shows Potent Anti-Leukemia Activity on Chronic Myeloid Leukemia In Vitro and In Vivo by Regulating MAPK/ERK/JNK and JAK2/STAT3 /AKT Signalings

Abstract

PurposeTo explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms.MethodCML cells were incubated with various concentration of Icaritin for 48 hours, the cell proliferation was analyzed by MTT and the apoptosis was assessed with Annexin V and Hoechst 33258 staining. Cell hemoglobinization was determined. Western blotting was used to evaluate the expressions of MAPK/ERK/JNK signal pathway and Jak-2/Phorpho-Stat3/Phorsph-Akt network-related protein. NOD-SCID nude mice were applied to demonstrate the anti-leukemia effect of Icaritin in vivo.ResultsIcaritin potently inhibited proliferation of K562 cells (IC50 was 8 µM) and primary CML cells (IC50 was 13.4 µM for CML-CP and 18 µM for CML-BC), induced CML cells apoptosis and promoted the erythroid differentiation of K562 cells with time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis. In mouse leukemia model, Icaritin could prolong lifespan of NOD-SCID nude mice inoculated with K562 cells as effective as Imatinib without suppression of bone marrow. Icaritin could up-regulate phospho-JNK or phospho-C-Jun and down-regulate phospho-ERK, phospho-P-38, Jak-2, phospho-Stat3 and phospho-Akt expression with dose- or time-dependent manner. Icaritin had no influence both on c-Abl and phospho-c-Abl protein expression and mRNA levels of Bcr/Abl.ConclusionIcaritin from Chinese herb medicine may be a potential anti-CML agent with low adverse effect. The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML.

Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression

“…Icaritin caused sustained ERK1/2 activation and induced apoptosis in human endometrial cancer cells, and icaritin could also induce apoptosis in HepG2 cells via the JNK1 signaling pathway. Icaritin may be useful as an alternative therapeutic choice for imatinib-resistant forms of CML [23] .…”

“…Based on the inhibitory effects of icaritin on the expression of MMP-2 and MMP-9, icaritin may have potential as a treatment for patients with advanced osteosarcoma. According to previous studies, the mechanisms underlying the antitumor activity of icaritin include the induction of apoptosis by multiple signaling pathways [5,6,20,23] . The caspase (cysteinyl aspartate specific protease) family is involved in apoptotic signal transduction and plays an important role in regulating apoptosis [37,38] .…”

Expression and functions of the STAT3-SCLIP pathway in chronic myeloid leukemia cells

“…As already mentioned, STAT3 is a member of the JAK/STAT pathway that regulates CML (12). It also participates in the phosphatidylinositol 3-kinase/mammalian target of rapamycin/STAT3 pathway to regulate cell viability in breast cancer stem-like cells (29).…”

“…Signal transducers and activators of transcription (STAT) are important factors among these pathways, which are activated in blood cells from acute myeloid leukemia and CML (11). Among the STAT family members, STAT3 has been demonstrated to function in CML via the Janus activated kinase (JAK)/STAT pathway (12) and helps to mediate the anticancer activity of certain phytochemicals in the combination therapy of CML (13). Furthermore, its contribution to the regulation of the migration and viability of CML cells is indicated by molecular target studies (14,15).…”

Icaritin acts synergistically with epirubicin to suppress bladder cancer growth through inhibition of autophagy

“…Previous studies reported that ERK and AKT signaling are the dominant pathway for icaritin to inhibit cancer cells growth in chronic myeloid leukemia, endometrial cancer renal cell carcinoma and breast cancer cells (15,17,18,35). Moreover, Li et al revealed that the apoptosis of human hepatoma was also induced via icariin treatment with ROS/JNK-dependent mitochondrial pathway (30).…”