curcumin and dehydroxymethylepoxyquinomicin

Breast cancer continues to cause significant burden in global health morbidity and mortality. Triple-negative breast cancers (TNBCs) are highly aggressive with poor prognosis and are characterized by lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (Her-2). TNBCs are often resistant to cytotoxic chemotherapy and pose major difficulty in achieving personalized medicine due to their molecular heterogeneity. There is increasing evidence that the aberrant activation of nuclear factor (NF)-κB signaling is a frequent characteristic of TNBCs. We evaluated the effects of different potential NF-κB inhibitors, such as bisindolylmaleimide I (BIS, a selective protein kinase C [PKC] inhibitor), MG132 (a proteasome inhibitor), curcumin (endowed with pleiotropic activities), and dehydroxymethylepoxyquinomicin (an inhibitor of NF-κB translocation into the nucleus) on the constitutive activation of NF-κB present in three TNBC cell lines (SUM 149, SUM 159, and MDA-MB-231). We also evaluated whether MDA-9/Syntenin plays a role in NF-κB activation, as observed in other cancer types. Indeed, silencing experiments with a siRNA anti-MDA-9/Syntenin produced a very strong reduction of NF-κB activation in all the three TNBC cell lines. We conclude that different approaches targeting NF-κB activation might potentially prove useful for innovation in anticancer drug development for TNBCs. Further research that bridge preclinical and clinical investigations with NF-κB inhibitors would be timely and warranted.

Topics: Benzamides; Cell Line, Tumor; Curcumin; Cyclohexanones; Female; Humans; NF-kappa B; Precision Medicine; Signal Transduction; Triple Negative Breast Neoplasms

Cancer cells may often support their own growth, survival, and drug resistance by autocrine/paracrine loops based on the production of different factors; results from us and others have shown that similar interleukin-6 (IL-6)-related loops are operative in multiple myeloma and prostate or renal cancer. Because this aspect has not been investigated in detail for hepatocellular carcinoma (HCC), we have examined it in HA22T/VGH cells. These differ from other primary liver cancer cell lines (that is, HepG2, HuH-6, and HuH-7) in that enzyme-linked immunosorbent assay (ELISA) showed the HA22T/VGH cells to secrete remarkable amounts of IL-6 (16.8 ng/10(6) cells/24 h); this production, due to constitutive activation of NF-kappaB, is inhibited by agents like curcumin and dehydroxymethylepoxyquinomicin (DHMEQ), which interfere with the transcription factor. Flow cytometry, ELISA, mRNA, and Western blotting analyses were performed to characterize the status of the IL-6 receptor in HA22T/VGH cells. Two transmembrane glycoproteins that form the functional IL-6 receptor have been identified: the ligand-binding gp80 and the signal-transducer gp130. Soluble forms of gp80 also trigger membrane gp130 signaling when complexed with IL-6, while soluble forms of gp130 inhibit the same process. Our results showed that HA22T/VGH cells express gp130 at their surface, but release only traces of its soluble form. For gp80, the cells produced the mRNAs of both its membrane and soluble form. However, in immunoblotting they exhibited a very faint content of the same subunit, which, in addition, was neither expressed at the cell surface nor secreted. In MTT assays, incubation with a neutralizing anti-IL-6 antibody for up to 7 days did not affect the growth of HA22T/VGH cells. Also, other specific anti-IL-6 approaches (siRNA or AODN) failed to produce this result. In conclusion, autostimulatory loops mediated by IL-6 are less likely to occur in HCC than in other kinds of cancer. However, since release of IL-6 is frequent in HCC, especially in its more advanced stages, the use of agents like curcumin or DHMEQ might be beneficial to counteract its adverse systemic effects (e.g., cachexia).

Topics: Antibodies; Benzamides; Carcinoma, Hepatocellular; Cell Membrane; Curcumin; Cyclohexanones; Cytokine Receptor gp130; Humans; Interleukin-6; Liver Neoplasms; Models, Biological; NF-kappa B; Receptors, Interleukin-6; RNA, Small Interfering; Tumor Cells, Cultured