CRISPR/dCas9 systems can precisely control endogenous gene expression without interrupting host genomic sequence and have provided a novel and feasible strategy for the treatment of cancers at the transcriptional level. However, development of CRISPR/dCas9‐based anti‐cancer therapeutics remains challenging due to the conflicting requirements for the design of the delivery system: a cationic and membrane‐binding surface facilitates the tumor accumulation and cellular uptake of the CRISPR/dCas9 system, but hinders the circulating stability in vivo. Here, a multistage delivery nanoparticle (MDNP) that can achieve tumor‐targeted delivery of CRISPR/dCas9 systems and restore endogenous microRNA (miRNA) expression in vivo is described. MDNP is designed as a core‐shell structure in which the shell is made of a responsive polymer that endows MDNP with the capability to present different surface properties in response to its surrounding microenvironment, allowing the MNDP overcoming multiple physiological barriers and delivering the payload to tumor tissues with an optimal efficiency. Systemic administration of MDNP/dCas9‐miR‐524 to tumor‐bearing mice achieved effective upregulation of miR‐524 in tumors, leading to the simultaneous interferences of multiple signal pathways related to cancer cell proliferation and presenting remarkable tumor growth retardation, suggesting the feasibility of utilizing MDNP to achieve tumor‐targeting delivery of CRISPR/dCas9 with sufficient levels to realize its therapeutic effects.

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...

Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment.

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