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    • AP and NF B activation is inhibited by curcumin

    2022-07-18

    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 C598-0466 australia 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.