Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • AP and NF B activation is

    2021-12-03

    AP-1 [16], [17] and NF-κB activation is inhibited by curcumin (diferuloylmethane) [18], [19], the yellow component of Curcuma longa that gives curry its colour and flavour. Curcumin has shown anti-inflammatory and antioxidant properties [20], [21], [22], [23], [24], [25], [26] due to the inhibition of cyclooxygenase 2 and lipoxygenase [27], [28]. Curcumin inhibits tumour initiation (by benz[a]pyrene and 7,12-dimethylbenz[a]anthracene [29]) and promotion (by phorbol esters) thus showing anticarcinogenic properties [30], [31].
    Materials and methods
    Results
    Discussion Curcumin is a compound known for its antioxidant and anticarcinogenic properties [20], [21], [22], [23], [24], [25], [26]. It has also been shown to have an inhibitory effect on AP-1 and NF-κB activation. We investigated here its effects on GSTP1-1 expression in leukemia cell lines. Indeed, GSTP1-1 was found to be related to carcinogenesis and resistance to anticancer drugs [38]. The implication of NF-κB and AP-1 [3], [39] in GSTP1-1 regulation was demonstrated and the use of curcumin in leukemia could lead to a valuable therapeutic tool. We show here that treatment by the chemopreventive agent curcumin of K562 CID 755673 sale leads to increased cell death compared to cells cultured without curcumin. Apoptosis is characterised by caspase activation [40]. Mukhopadhyay et al.[41] previously showed that curcumin induced apoptosis in human androgen-dependent LNCaP as well as androgen-independent DU145 human prostate cancer cell lines by down-regulating the expression of Bcl-2 and Bcl-XL and the activation of the pro-caspases 3 and 8. Similar results were obtained by Bush et al.[42] by using a melanoma cell model. Our results agree with the data obtained by Barthi et al.[43] where in multiple myeloma cells curcumin induces caspases 7 and 9. We show here that apoptosis can be induced by curcumin in K562 cells through activation of caspases 8 and 9 indicating that both the mitochondrial and death receptor pathways are activated. K562 cells carry the Philadelphia chromosome with the Bcr-Abl fusion gene. The Bcr-Abl oncoprotein activates several pathways implicated in carcinogenesis such as Myc, Ras, c-Raf, MAPK/ERK, SAPK/JNK, Stat, NF-κB, PI-3 kinase and c-Jun due to a constitutively activated tyrosine kinase activity. In cells carrying such a translocation, apoptosis is decreased and cell proliferation is upregulated. In K562 cells, classical apoptosis can only be induced in cells by inhibiting Ras, Raf, PI3K, Akt, Jun and Myc [44]. In our hands, inhibition of constitutively active AP-1 and NF-κB in K562 by curcumin leads to caspase 8 and 9-dependent cell death. Similar results were obtained by Barthi et al.[43] in human prostate cancer cells and Piwocka et al. in Jurkat T cells [45]. As AP-1 and NF-κB binding activities are correlated to GSTP1-1 expression, inhibition of those transcription factors by curcumin should induce a reduction of GSTP1-1 expression at the mRNA level. Singhal et al.[46] previously showed a weak induction by curcumin of the alpha-class hGST 5.8 isozyme, indicated by an increased activity toward 4-hydroxynonenal. We show here a substantial reduction of GSTP1-1 mRNA expression in human K562 chronic myelogenous leukemia cells. It is of interest to note that with 66%, GSTP1-1 is the major GST isoform expressed by K562 and that the expression of this isoform is correlated to chemoresistance in leukemia [47], breast and ovary cancer [5], [6], [7], [8], [9]. Morales et al.[48] previously demonstrated the effect of the proinflammatory cytokine TNFα [49] on the expression of another key enzyme of the glutathione pathway, gamma-glutamyl cysteine synthetase (γGCS). TNFα was able to induce the γGCS mRNA expression by 70% in a rat hepatocyte model. In this model, TNFα was able to induce NF-κB as well as AP-1 transcription factors. As we and other groups recently showed the importance of both AP-1 [33] and NF-κB sites in the regulation of the GSTP1-1 expression, inhibition of DNA bindings of both transcription factors by curcumin should be responsible for a decrease in GSTP1-1 gene expression and thus could contribute to reduce drug resistance and carcinogenesis due to GSTP1-1 activity.