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Icaritin suppresses multiple myeloma, by inhibiting IL-6/JAK2/STAT3.

Zhu S, Wang Z, Li Z, Peng H, Luo Y, Deng M, Li R, Dai C, Xu Y, Liu S, Zhang G - Oncotarget (2015)

Bottom Line: In contrast, icaritin had low or no cytotoxic effect on normal hematopoiesis.We also demonstrated that in MM xenograft mouse models, icaritin suppressed tumor growth and decreased serum IL-6 and IgE levels, but did not show adverse reactions such as body weight loss.The anti-MM activity of icaritin was mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Institute of Molecular Hematology, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan, China.

ABSTRACT
Icaritin is an active prenylflavonoid derived from Epimedium genus, a traditional Chinese medicine. Icaritin has a wide range of pharmacological and biological activities, including cardiovascular function improvement, hormone regulation and antitumor activity. Here, we investigated the effect of icaritin on multiple myeloma (MM) in vitro and in vivo. Icaritin inhibited cell growth of MM cell line and primary MM cells. In contrast, icaritin had low or no cytotoxic effect on normal hematopoiesis. We also demonstrated that in MM xenograft mouse models, icaritin suppressed tumor growth and decreased serum IL-6 and IgE levels, but did not show adverse reactions such as body weight loss. The anti-MM activity of icaritin was mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling. We suggest that icaritin can be further tested in clinical trials in MM.

No MeSH data available.


Related in: MedlinePlus

Anti-MM effect of icaritin was associated with decreasing IL-6 level and inhibiting the downstream signalingsA. Icaritin decreased significantly the autocrine IL-6 levels at time-dependent (24 h, 48 h, 72 h) or dose-dependent (2–32 μM) manner in U266 cells. Results represent the mean of three independent experiments. B. Effect of icaritin (16 μM), dexamethasone (10 μM) on autocrine IL-6 in U266 cells. Cells were treated with the different agents for 24, 48 or 72 hours. Data portrayed are the mean of separate experiments with the SD showed. Statistical significance was determined by 2-tail Student's t-test. **p < 0.01; ***p < 0.001. C. Icaritin (2–32 μM) up-regulated the expression of p-JNK and p-ERK in U266 cells (48 h) (western blot results). D. U266 cells were treated with icaritin at indicated doses for 24 h, p-JAK2 and p-STAT3 were detected by Western blot.the results showed Icaritin inhibited the expression of p-JAK2 and p-STAT3.
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Figure 3: Anti-MM effect of icaritin was associated with decreasing IL-6 level and inhibiting the downstream signalingsA. Icaritin decreased significantly the autocrine IL-6 levels at time-dependent (24 h, 48 h, 72 h) or dose-dependent (2–32 μM) manner in U266 cells. Results represent the mean of three independent experiments. B. Effect of icaritin (16 μM), dexamethasone (10 μM) on autocrine IL-6 in U266 cells. Cells were treated with the different agents for 24, 48 or 72 hours. Data portrayed are the mean of separate experiments with the SD showed. Statistical significance was determined by 2-tail Student's t-test. **p < 0.01; ***p < 0.001. C. Icaritin (2–32 μM) up-regulated the expression of p-JNK and p-ERK in U266 cells (48 h) (western blot results). D. U266 cells were treated with icaritin at indicated doses for 24 h, p-JAK2 and p-STAT3 were detected by Western blot.the results showed Icaritin inhibited the expression of p-JAK2 and p-STAT3.

Mentions: It has been shown that IL-6-mediated autocrine loop in U266 cells was involved in the resistance to dexamethasone (DXM)-induced apoptosis [27]. Baicalein, a major flavonoid derived from Scutellaria radix, was able to inhibit IL-6 expression in U266 cells [20]. To explore the potential mechanisms regulating the effects of icaritin on U266 cells, and determine if anti-MM activity of icaritin is related to the inhibition of IL-6 mediated autocrine loop, we examined several major oncogenic signaling pathways, including IL-6, JAK2, STAT3, and two members of mitogen-activated protein kinase (MAPK) family: JNK and ERK. Our results demonstrated that icaritin was able to reduce significantly the levels of IL-6 in cultured U266 cells supernatant with dose- or time-dependent manner (Figure 3A). Of note, compared with DXM-treatment, icaritin exhibited a persistent inhibition on IL-6 levels and reversed the DXM-resistance of U266 cells to a certain extent (Figure 3B). Although icaritin had no effect on total JNK and ERK proteins, evidently it up-regulated expression of phospho-JNK (p-JNK) and phospho-ERK (p-ERK) (Figure 3C).


Icaritin suppresses multiple myeloma, by inhibiting IL-6/JAK2/STAT3.

Zhu S, Wang Z, Li Z, Peng H, Luo Y, Deng M, Li R, Dai C, Xu Y, Liu S, Zhang G - Oncotarget (2015)

Anti-MM effect of icaritin was associated with decreasing IL-6 level and inhibiting the downstream signalingsA. Icaritin decreased significantly the autocrine IL-6 levels at time-dependent (24 h, 48 h, 72 h) or dose-dependent (2–32 μM) manner in U266 cells. Results represent the mean of three independent experiments. B. Effect of icaritin (16 μM), dexamethasone (10 μM) on autocrine IL-6 in U266 cells. Cells were treated with the different agents for 24, 48 or 72 hours. Data portrayed are the mean of separate experiments with the SD showed. Statistical significance was determined by 2-tail Student's t-test. **p < 0.01; ***p < 0.001. C. Icaritin (2–32 μM) up-regulated the expression of p-JNK and p-ERK in U266 cells (48 h) (western blot results). D. U266 cells were treated with icaritin at indicated doses for 24 h, p-JAK2 and p-STAT3 were detected by Western blot.the results showed Icaritin inhibited the expression of p-JAK2 and p-STAT3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496367&req=5

Figure 3: Anti-MM effect of icaritin was associated with decreasing IL-6 level and inhibiting the downstream signalingsA. Icaritin decreased significantly the autocrine IL-6 levels at time-dependent (24 h, 48 h, 72 h) or dose-dependent (2–32 μM) manner in U266 cells. Results represent the mean of three independent experiments. B. Effect of icaritin (16 μM), dexamethasone (10 μM) on autocrine IL-6 in U266 cells. Cells were treated with the different agents for 24, 48 or 72 hours. Data portrayed are the mean of separate experiments with the SD showed. Statistical significance was determined by 2-tail Student's t-test. **p < 0.01; ***p < 0.001. C. Icaritin (2–32 μM) up-regulated the expression of p-JNK and p-ERK in U266 cells (48 h) (western blot results). D. U266 cells were treated with icaritin at indicated doses for 24 h, p-JAK2 and p-STAT3 were detected by Western blot.the results showed Icaritin inhibited the expression of p-JAK2 and p-STAT3.
Mentions: It has been shown that IL-6-mediated autocrine loop in U266 cells was involved in the resistance to dexamethasone (DXM)-induced apoptosis [27]. Baicalein, a major flavonoid derived from Scutellaria radix, was able to inhibit IL-6 expression in U266 cells [20]. To explore the potential mechanisms regulating the effects of icaritin on U266 cells, and determine if anti-MM activity of icaritin is related to the inhibition of IL-6 mediated autocrine loop, we examined several major oncogenic signaling pathways, including IL-6, JAK2, STAT3, and two members of mitogen-activated protein kinase (MAPK) family: JNK and ERK. Our results demonstrated that icaritin was able to reduce significantly the levels of IL-6 in cultured U266 cells supernatant with dose- or time-dependent manner (Figure 3A). Of note, compared with DXM-treatment, icaritin exhibited a persistent inhibition on IL-6 levels and reversed the DXM-resistance of U266 cells to a certain extent (Figure 3B). Although icaritin had no effect on total JNK and ERK proteins, evidently it up-regulated expression of phospho-JNK (p-JNK) and phospho-ERK (p-ERK) (Figure 3C).

Bottom Line: In contrast, icaritin had low or no cytotoxic effect on normal hematopoiesis.We also demonstrated that in MM xenograft mouse models, icaritin suppressed tumor growth and decreased serum IL-6 and IgE levels, but did not show adverse reactions such as body weight loss.The anti-MM activity of icaritin was mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Institute of Molecular Hematology, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan, China.

ABSTRACT
Icaritin is an active prenylflavonoid derived from Epimedium genus, a traditional Chinese medicine. Icaritin has a wide range of pharmacological and biological activities, including cardiovascular function improvement, hormone regulation and antitumor activity. Here, we investigated the effect of icaritin on multiple myeloma (MM) in vitro and in vivo. Icaritin inhibited cell growth of MM cell line and primary MM cells. In contrast, icaritin had low or no cytotoxic effect on normal hematopoiesis. We also demonstrated that in MM xenograft mouse models, icaritin suppressed tumor growth and decreased serum IL-6 and IgE levels, but did not show adverse reactions such as body weight loss. The anti-MM activity of icaritin was mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling. We suggest that icaritin can be further tested in clinical trials in MM.

No MeSH data available.


Related in: MedlinePlus