Wogonoside induces cell cycle arrest and differentiation by affecting expression and subcellular localization of PLSCR1 in AML cells

Abstract

Key Points• Wogonoside induces cell cycle arrest and differentiation. • Wogonoside acts by changing PLSCR1 expression and subcellular localization in the nucleus and by PLSCR1-related molecular events.Wogonoside is the main flavonoid component derived from the root of Scutellaria baicalensis Georgi. It is a popular Chinese herbal medicine with the potential to treat hematologic malignancies. In this study, we investigated the anticancer effects of wogonoside in acute myeloid leukemia (AML) cell lines and primary patient-derived AML cells. Wogonoside exerted antiproliferative properties both in vitro and in vivo. Furthermore, it efficiently inhibited the proliferation of U937 and HL-60 cells through the induction of G 1 phase arrest and the promotion of differentiation. We also demonstrated that wogonoside significantly increased the transcription of phospholipid scramblase 1 (PLSCR1) due to its influence on the expression of cell cycle-and differentiation-related genes, including the upregulation of p21waf1/cip1 and downregulation of the oncogenic protein c-Myc. Wogonoside also promoted PLSCR1 trafficking into the nucleus and facilitated its binding to the inositol 1,4,5-trisphosphate receptor 1 (IP3R1) promoter, thus increasing the expression of IP3R1. Finally, inhibition of PLSCR1 expression with small interfering RNA partially blocked wogonoside-induced cell cycle arrest and differentiation and disturbed the wogonosideassociated molecular events. The results of this study therefore suggest that wogonoside may represent a therapeutic candidate for the treatment of AML. (Blood. 2013;121(18):3682-3691) Introduction Acute myeloid leukemia (AML) comprises a genetically and clinically heterogeneous group of aggressive hematological neoplasms. 1Continuing research into the pathogenesis and heterogeneity of AML has resulted in the development of several potentially useful therapeutic agents.2 However, despite some advances in the treatment of AML, therapies have not changed significantly in the past 20 years. Further research is thus warranted to identify effective agents and develop new therapeutic strategies for the treatment of this deadly disease. Flavonoids possess diverse biological and pharmaceutical properties and have been subjected to extensive investigations as likely candidates for cancer treatment. Scutellaria baicalensis Georgi (huang qin) is 1 of the most popular and multipurpose traditional Chinese medicinal herbs, and it has a high flavonoid content. 4 Wogonin, a flavonoid extracted from S. baicalensis, has several biological effects including antioxidant, anti-inflammatory, antiviral, neuroprotective, anxiolytic, and anticancer activities. 5 It has been shown to possess antitumor effects in various cancer cells, 6 including antiproliferation, cell cycle arrest, induction of apoptosis and differentiation, inhibition of angiogenesis, anti-invasion, and increased sensitivity to apoptosis. Moreover, wogonin has shown therapeutic potential for the treatment of hematologic malignancies. 7 Flavonoid agl...

Wogonoside induces apoptosis in Bel-7402, a hepatocellular carcinoma cell line, by regulating Bax/Bcl-2

“…The anticancer effect of Scutellaria baicalensis extract has recently become a topic of interest. Moreover, a number of in vitro studies suggest that the extract of Scutellaria baicalensis inhibits the growth of various cancer cell lines through specific biological signaling pathways, including apoptosis, angiogenesis and inhibition of the androgen receptor (15,16,(18)(19)(20)(21)(22)(23).…”

Natural products against hematological malignancies and identification of their targets

“…The silencing of PLSCR1 by its sequence-specific siRNA blocks the wogonoside-induced increase in p21 waf1/cip1 and decrease in c-Myc [96]. PLSCR1 was found inside the nuclei in U937 and HL-60 cells after treatment with wogonoside.…”

“…Indeed, wogonoside exerts an in vitro antiproliferative activity in the AML cell lines U937, HL-60, and primary AML cells, and it inhibits the proliferation of U937 xenografts and prolongs survival in AML-bearing mice in vivo. Wogonoside-induced cell cycle arrest is associated with the downregulation of cyclin D1 and CDK4, and it also induces the differentiation of AML cell lines and primary AML cells [96].…”

“…Employinging an inducible PLSCR1-expressing myeloid leukemia U937 cell line, we showed that inducible PLSCR1 expression arrests the proliferation at the G 1 phase and induces granulocyte-like differentiation with increased sensitivity to etoposide-induced apoptosis of the genetically engineered cells [103]. Of great interest is the fact that PLSCR1 expression can also be induced during wogonin and wogonoside-induced differentiation of AML-derived cell lines via dramatically increased PKC phosphorylation at Ser 643 [92,96]. Moreover, p21…”

Natural Compounds: Molecular Weapons against Leukemia’s

“…Besides, wogonoside affects differentiation, acting on human AML cells in vitro and in vivo. In particular, wogonoside induces the monocytic differentiation of lymphoma cell line U937 and leukemic cell line HL60 [76].…”