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Publications (4)11.25 Total impact

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    ABSTRACT: N-Benzoyl-O-(N'-(1-benzyloxycarbonyl-4-piperidiylcarbonyl)-D-phenylalanyl)-D-phenylalaninol (BBP), a novel synthesized asperphenamate derivative with the increased solubility, showed growth inhibitory effect on human breast carcinoma MCF-7 cells in a time- and concentration-dependent manner. The growth inhibitory effect of BBP was associated with induction of autophagy, which was demonstrated by the development of acidic vesicular organelles, cleavage of LC3 and upregulation of Atg4 in BBP-treated MCF-7 cells. Since the application of Atg4 siRNA totally blocked the cleavage of LC3, we demonstrated a central role of Atg4 in BBP-induced autophagy. The further studies showed that BBP increased the levels of reactive oxygen species (ROS), and pretreatment with NAC effectively blocked the accumulation of ROS, autophagy and growth inhibition triggered by BBP. Moreover, BBP induced the activation of JNK, and JNK inhibitor SP600125 reversed autophagy, the increase of Atg4 levels, conversion of LC3 and growth inhibition induced by BBP. Knockdown of JNK by siRNA efficiently inhibited ROS production and autophagy, but antioxidant NAC failed to block JNK activation induced by BBP, indicating that JNK activation may be a upstream signaling of ROS and should be a core component in BBP-induced autophagic signaling pathway. These results suggest that BBP produces its growth inhibitory effect through induction of the autophagic cell death in MCF-7 cells, which is modulated by a JNK-dependent Atg4 upregulation involving ROS production.
    Toxicology and Applied Pharmacology 06/2012; 263(1):21-31. · 3.98 Impact Factor
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    ABSTRACT: Andrographolide, a principal diterpenoid lactone isolated from the traditional herbal medicine Andrographis paniculata, has been reported to show anti-tumor activity. Since the high lipid solubility of andrographolide permits it to penetrate the blood-brain barrier and concentrate in the brain, we hypothesized that andrographolide may be a potential chemotherapeutic agent for the treatment of glioblastomas. To clarify this point, we investigated the growth inhibitory effect and mechanisms of actions of andrographolide on human glioblastoma U251 and U87 cells. MTT assay and trypan blue exclusion assay were used to investigate the proliferation inhibitory and cytotoxic effects of andrographolide, respectively. Cell cycle distribution was analyzed using flow cytometry. Apoptosis analysis proceeded by detecting the cleavage of caspase-3. The levels of proteins were probed by Western blotting. The results showed that non-toxic concentrations of andrographolide inhibited the proliferation of human glioblastoma cells through induction of G2/M arrest, which was accompanied by down-regulating Cdk1 and Cdc25C proteins. Additionally, andrographolide decreased the activity of PI3K/Akt signaling, as demonstrated by down-regulation of the expression of phos-PI3K, phos-Akt, phos-mTOR and phos-p70s6k in U251 and U87 cells. Furthermore, additive effects on the proliferation inhibition, G2/M arrest and down-regulation of G2/M phase-related proteins were observed, when a combined treatment of andrographolide with PI3K inhibitor LY294002 was used in U251 and U87 cells. We prove that andrographolide inhibits the proliferation of human glioblastoma cells via inducing G2/M arrest, which is mediated by inhibiting the activity of PI3K/Akt signaling.
    Life sciences 05/2012; 90(25-26):962-7. · 2.56 Impact Factor
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    ABSTRACT: β-eudesmol, a natural sesquiterpenol present in a variety of Chinese herbs, is known to inhibit the proliferation of human tumor cells. However, the molecular mechanisms of the effect of β-eudesmol on human tumor cells are unknown. In the present study, we report the cytotoxic effect of β-eudesmol on the human leukemia HL60 cells and its molecular mechanisms. The cytotoxic effect of β-eudesmol on HL60 cells was associated with apoptosis, which was characterized by the presence of DNA fragmentation. β-eudesmol-induced apoptosis was accompanied by cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase; downregulation of Bcl-2 expression; release of cytochrome c from mitochondria; and decrease in mitochondrial membrane potential (MMP). Activation of c-Jun N-terminal kinases (JNK) mitogen-activated protein kinases was observed in β-eudesmol-treated HL60 cells, and the inhibitor of JNK blocked the β-eudesmol-induced apoptosis, downregulation of Bcl-2, and the loss of MMP. These data suggest that β-eudesmol induces apoptosis in HL60 cells via the mitochondrial apoptotic pathway, which is controlled through JNK signaling. Copyright © 2012 John Wiley & Sons, Ltd.
    Phytotherapy Research 05/2012; · 2.07 Impact Factor
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    ABSTRACT: In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.
    Bioorganic & medicinal chemistry letters 03/2012; 22(6):2216-20. · 2.65 Impact Factor