Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation

Han, Jianzhong; Kurita, Yui; Isoda, Hiroko

doi:10.1007/s10616-013-9592-0

Cited by 19 publications

(12 citation statements)

References 26 publications

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“…It was reported that genistein inhibited cancer cell growth by attenuating the negative effect of epidermal growth factor (EGF) on FOXO3 (Qi et al, 2011); Moreover, genistein may prevent cell-cycle progression by decreasing Cyclin B1, checkpoint kinase 2 (Chk2) and proliferating cell nuclear antigen (PCNA), while up-regulating the expression of p21 (Fan et al, 2010;Han et al, 2013). It was suggested that genistein might reduce angiogenesis via suppressing the expression of vascular endothelial growth factor (VEGF) (Fan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells

Qin¹,

Teng²,

Zhu

et al. 2015

Pharmaceutical Biology

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Context: Genistein inhibits the proliferation and induces apoptosis of colorectal cancer cells; however, the underling molecular mechanisms remain to be determined. Aim: The aim of this study was to investigate whether genistein reduces cell viability by suppressing the phosphorylation of AKT and activating the mitochondrial apoptosis pathway in colorectal cancer cells. Materials and methods: The anti-proliferative effects of genistein (0, 25, 50, and 100 mM) on HCT-116 and LoVo cells were assessed using MTT assay. Genistein-induced apoptosis was measured by Hoechst 33258 staining and flow cytometry. The mRNA level of Bax was detected by real-time PCR. The protein levels of Bax, total Akt, and phosphorylated Akt were assessed by western blot. Results: The IC 50 values of genistein were 690, 135, and 61 mM in HCT-116 cells and 204, 135, and 93 mM in LoVo cells after treatment for 24, 48, and 72 h, respectively. After treatment with different concentrations of genistein (0, 25, 50, and 100 mM) for 48 h, the early apoptotic cells in HCT-116 increased from 1.99% ± 0.55% to 6.78% ± 2.12%, 23.16% ± 3.87%, and 36.99% ± 3.76%, respectively. The same concentrations of genistein increased the early apoptotic cells in LoVo from 2.56% ± 1.42% to 3.21% ± 1.52%, 18.22% ± 3.56%, and 23.56% ± 3.02%, respectively. Moreover, genistein increased the mRNA and protein levels of Bax, while it inhibited the phosphorylation of Akt in HCT-116 cells. Conclusion: Genistein inhibited cell proliferation and induced apoptosis of colorectal cancer cells. Genistein induced the mitochondrial pathway of apoptosis in HCT-116 cells by inhibiting phosphorylation of Akt.

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Section: Introductionmentioning

confidence: 99%

Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells

Qin¹,

Teng²,

Zhu

et al. 2015

Pharmaceutical Biology

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“…Additionally, genistein has been reported to induce G2/M cell cycle arrest, which results in pronounced opening of the nuclear pores allowing better nuclear transport of gene delivery vectors [26–28]. Thus, we evaluated the nuclear accumulation of the AAV2 transgene cassette, since gene expression by RGD4C-AAVP is mediated through its AAV2 transgene cassette.…”

Section: Resultsmentioning

confidence: 99%

“…The increased nuclear accumulation of AAVP genome, upon genistein pre-treatment, provides an additional mechanism that could further explain the improved AAVP-mediated gene expression by genistein. One explanation is that pretreatment with genistein enhances the size of the nuclear pores, as genistein was reported to induce G2/M cell cycle arrest, during which nuclear localisation of gene therapy vectors can be enhanced [26–28]. …”

Section: Discussionmentioning

confidence: 99%

“…For instance, the ability of genistein to inhibit the chymotrypsin-like activity of proteasome [25], can be used to prevent AAVP degradation by the proteasome. Moreover, the ability of genistein to induce G2/M cell cycle arrest could result in increased nuclear transport of gene therapy vectors [26–28]. Consequently, taking into account the safety of genistein, its anticancer activity and interference with cellular pathways, we hypothesized that combination of genistein with our tumor-targeted RGD4C-AAVP biotherapeutic particle would lead to enhanced tumor cell killing along with reduced toxicity.…”

Section: Introductionmentioning

confidence: 99%

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The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction

et al. 2016

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Gene therapy has long been regarded as a promising treatment for cancer. However, cancer gene therapy is still facing the challenge of targeting gene delivery vectors specifically to tumors when administered via clinically acceptable non-invasive systemic routes (i.e. intravenous). The bacteria virus, bacteriophage (phage), represents a new generation of promising vectors in systemic gene delivery since their targeting can be achieved through phage capsid display ligands, which enable them to home to specific tumor receptors without the need to ablate any native eukaryotic tropism. We have previously reported a tumor specific bacteriophage vector named adeno-associated virus/phage, or AAVP, in which gene expression is under a recombinant human rAAV2 virus genome targeted to tumors via a ligand-directed phage capsid. However, cancer gene therapy with this tumor-targeted vector achieved variable outcomes ranging from tumor regression to no effect in both experimental and natural preclinical models. Herein, we hypothesized that combining the natural dietary genistein, with proven anticancer activity, would improve bacteriophage anticancer safe therapy. We show that combination treatment with genistein and AAVP increased targeted cancer cell killing by AAVP carrying the gene for Herpes simplex virus thymidine kinase (HSVtk) in 2D tissue cultures and 3D tumor spheroids. We found this increased tumor cell killing was associated with enhanced AAVP-mediated gene expression. Next, we established that genistein protects AAVP against proteasome degradation and enhances vector genome accumulation in the nucleus. Combination of genistein and phage-guided virotherapy is a safe and promising strategy that should be considered in anticancer therapy with AAVP.

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“…It has been documented that genistein may induce a G2/M arrest in different cancer cell lines (Liu et al 2013b;Han et al 2013) or arrest mouse fibroblast at an G0/G1 phase of the cell cycle (Kuzumaki et al 1998). It has been documented that genistein may induce a G2/M arrest in different cancer cell lines (Liu et al 2013b;Han et al 2013) or arrest mouse fibroblast at an G0/G1 phase of the cell cycle (Kuzumaki et al 1998).…”

Section: Effect Of Isoflavones On Cell Proliferationmentioning

confidence: 99%

Critical Dietary Factors in Cancer Chemoprevention

Ullah¹,

Ahmad²

2016

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Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation

Cited by 19 publications

References 26 publications

Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells

Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells

The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction

Critical Dietary Factors in Cancer Chemoprevention

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