Wang WZ, Cheng J, Luo J, Zhuang SM.. Abrogation of G2/M arrest sensitizes curcumin-resistant hepatoma cells to apoptosis. FEBS Lett 582: 2689-2695

Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-Sen University, Xin Gang Xi Road 135, Guangzhou 510275, PR China.
FEBS Letters (Impact Factor: 3.17). 08/2008; 582(18):2689-95. DOI: 10.1016/j.febslet.2008.06.048
Source: PubMed


In this study, we showed that curcumin treatment resulted in activation of Chk1-mediated G2 checkpoint, which was associated with the induction of G2/M arrest and the resistance of cancer cells to curcumin-induced apoptosis. Further investigation revealed that inhibition of Chk1 significantly abrogated G2/M arrest and sensitized curcumin-resistant cells to apoptosis via upregulation of Bad and in turn the loss of mitochondrial membrane potential. These results indicate that Chk1-mediated G2/M arrest may serve as a mechanism for curcumin resistance and Chk1 represents a potential target for the reversal of this resistance. Our findings should be helpful for clinical application of curcumin.

Download full-text


Available from: Jiasen Cheng, Aug 06, 2015
  • Source
    • "Briefly, total RNA was isolated with the RNeasy mini kit (Qiagen, Hilden, Germany) and 100 ng of total RNA was used to synthesize a specific cDNA of miR-21 using the First-Strand cDNA Synthesis Kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. For detection of PTEN and PDCD4 expression, RNA was extracted and reverse transcribed as previously described [13]. The sequences of gene-specific PCR primers were: 5 0 -ACC GGC AGC ATC AAA TGT TT and 5 0 -AGT TCC ACC CCT TCC ATC TG for PTEN; 5 0 -TGA GAT TTA AGG GCT GGG CA and 5 0 -ACC ATC TCG ACT CAC TGC AA for PDCD4; 5 0 -CTC TGC TCC TCC TGTTCG AC and 5 0 -ACG ACC AAA TCC GTT GAC TC for glyceraldehydes-3-phosphate dehydrogenase (GAPDH). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cells are insensitive to BCR-ABL tyrosine kinase inhibitor imatinib, the underlying mechanisms remain largely unknown. Here, we showed that imatinib treatment induced significant upregulation of miR-21 and downregulation of PTEN in Ph+ ALL cell line Sup-b15. Transient inhibition of miR-21 resulted in increased apoptosis, PTEN upregulation and AKT dephosphorylation, whereas ectopic overexpression of miR-21 further conferred imatinib resistance. Furthermore, knockdown of PTEN protected the cells from imatinib-induced apoptosis achieved by inhibition of miR-21. Additionally, PI3K inhibitors also notably enhanced the effects of imatinib on Sup-b15 cells and primary Ph+ ALL cells similar to miR-21 inhibitor. Therefore, miR-21 contributes to imatinib resistance in Ph+ ALL cells and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to imatinib therapy.
    Preview · Article · Oct 2014 · Biochemical and Biophysical Research Communications
  • Source
    • "However, the physiological response triggered by curcumin depends on the cell type, the concentration of curcumin (IC50: 2-40 μg/ml) and the time of treatment [19]. For instance, curcumin treatment was reported to arrest cell growth at G2/M phase and induce apoptosis in human hepatoma cell line HepG2 [20,21], whereas G0/G1 as well as G1/S phase arrests were reported for various other cell lines [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Curcumin is a polyphenolic compound isolated from the rhizomes of the plant Curcuma longa and shows intrinsic anti-cancer properties. Its medical use remains limited due to its extremely low water solubility and bioavailability. Addressing this problem, drug delivery systems accompanied by nanoparticle technology have emerged. The present study introduces a novel nanocarrier system, so-called CurcuEmulsomes, where curcumin is encapsulated inside the solid core of emulsomes. CurcuEmulsomes are spherical solid nanoparticles with an average size of 286 nm and a zeta potential of 37 mV. Encapsulation increases the bioavailability of curcumin by up to 10,000 fold corresponding to a concentration of 0.11 mg/mL. Uptaken by HepG2 human liver carcinoma cell line, CurcuEmulsomes show a significantly prolonged biological activity and demonstrated therapeutic efficacy comparable to free curcumin against HepG2 in vitro - with a delay in response, as assessed by cell viability, apoptosis and cell cycle studies. The delay is attributed to the solid character of the nanocarrier prolonging the release of curcumin inside the HepG2 cells. Incorporation of curcumin into emulsomes results in water-soluble and stable CurcuEmulsome nanoformulations. CurcuEmulsomes do not only successfully facilitate the delivery of curcumin into the cell in vitro, but also enable curcumin to reach its effective concentrations inside the cell. The enhanced solubility of curcumin and the promising in vitro efficacy of CurcuEmulsomes highlight the potential of the system for the delivery of lipophilic drugs. Moreover, high degree of compatibility, prolonged release profile and tailoring properties feature CurcuEmulsomes for further therapeutic applications in vivo.
    Full-text · Article · Dec 2013 · Journal of Nanobiotechnology
  • Source
    • "Curcumin may induce apoptosis through p21Waf1/Cip1-dependent pathway [23]. Recently, curcumin has been reported to induce apoptosis in human hepatoma cell lines [24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) has been reported to regulate cellular microRNAs. The HCV core protein is considered to be a potential oncoprotein in HCV-related hepatocellular carcinoma, but HCV core-modulated cellular microRNAs are unknown. The HCV core protein regulates p21(Waf1/Cip1) expression. However, the mechanism of HCV core-associated p21(Waf1/Cip1) regulation remains to be further clarified. Therefore, we attempted to determine whether HCV core-modulated cellular microRNAs play an important role in regulating p21(Waf1/Cip1) expression in human hepatoma cells. Cellular microRNA profiling was investigated in core-overexpressing hepatoma cells using TaqMan low density array. Array data were further confirmed by TaqMan real-time qPCR for single microRNA in core-overexpressing and full-length HCV replicon-expressing cells. The target gene of microRNA was examined by reporter assay. The gene expression was determined by real-time qPCR and Western blotting. Apoptosis was examined by annexin V-FITC apoptosis assay. Cell cycle analysis was performed by propidium iodide staining. Cell proliferation was analyzed by MTT assay. HCV core protein up- or down-regulated some cellular microRNAs in Huh7 cells. HCV core-induced microRNA-345 suppressed p21(Waf1/Cip1) gene expression through targeting its 3' untranslated region in human hepatoma cells. Moreover, the core protein inhibited curcumin-induced apoptosis through p21(Waf1/Cip1)-targeting microRNA-345 in Huh7 cells. HCV core protein enhances the expression of microRNA-345 which then down-regulates p21(Waf1/Cip1) expression. It is the first time that HCV core protein has ever been shown to suppress p21(Waf1/Cip1) gene expression through miR-345 targeting.
    Full-text · Article · Apr 2013 · PLoS ONE
Show more