Carboplatin induces apoptotic cell death through downregulation of constitutively active nuclear factor-κB in human HPV-18 E6-positive HEp-2 cells
ABSTRACT Because the role of nuclear factor kappaB (NF-kappaB) is in cellular growth control and neoplasia, we explored the status of NF-kappaB and investigated its role in survival of human HPV-18 E6-positive HEp-2 cells. We observed accumulation of p65 in the nucleus. Moreover, without any external stimulus constitutive NF-kappaB DNA binding and transactivation activity were detected in HEp-2 cells. Treatment with NF-kappaB inhibitor curcumin (diferuloylmethane) and transient transfection of the mutant form of IkappaBalpha, IkappaBalpha super repressor (IkappaBalpha-SR), suppressed constitutive NF-kappaB activity as well as proliferation, suggesting that constitutive NF-kappaB activity is required for the survival of HEp-2 cells. Carboplatin treatment downregulated constitutive NF-kappaB activity and prevented nuclear retention of p65. Further, carboplatin also suppressed the constitutive IkappaBalpha phosphorylation leading to stabilization of IkappaBalpha protein in the cells. Carboplatin inhibited NF-kappaB binding to its response element present in Bcl-2 promoter resulting in downregulation of antiapoptotic Bcl-2 protein. Thus, our results for the first time indicate that constitutive NF-kappaB has a significant role in the survival of HPV-18 E6-positive HEp-2 cells. Moreover, inactivation of NF-kappaB is one of the mechanisms underlying the induction of carboplatin-mediated apoptosis in HPV-18 E6-positive cancer cells.
- SourceAvailable from: Apichart Suksamrarn[Show abstract] [Hide abstract]
ABSTRACT: Curcuma comosa Roxb. is a medicinal plant that has traditionally been used in Thailand for treatment of inflammation in postpartum uterine bleeding. The purpose of this study was to evaluate its anti-inflammatory effects using peripheral blood mononuclear cells (PBMC) and human pro-monocytic cell line (U937). Pretreatment with hexane or ethanol extract or two diarylhepatanoids (5-hydroxy-7-(4-hydroxyphenyl)-1-phenyl-(1E)-1-heptene and 7-(3,4-dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene) of C. comosa significantly decreased the release of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta, from phorbol-12-myristate-13-acetate (PMA)-stimulated PBMC and U937 cells. In PMA-stimulated U937 cells, the two C. comosa diarylhepatanoids reduced the expression of TNF-alpha and suppressed expression of IkappaB kinase and activation of nuclear factor kappa B. These results indicated that C. comosa and its diarylheptanoids have anti-inflammatory properties which could be exploited for clinical use.International Immunopharmacology 05/2007; 7(4):524-31. DOI:10.1016/j.intimp.2006.12.013 · 2.71 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Platinum drugs continue to be major chemotherapy drugs for cancer treatment. Nevertheless, acquired or intrinsic resistance to these compounds is common in human tumors. One important mechanism for this resistance is the avoidance of cells entering the apoptotic pathway. Nuclear factor-kappa B (NF-kappa B, NF-kappaB) is a pleiotropic transcription factor key in determining the death threshold of human cells. This factor is important in the final response of cells to platinum drugs, as exemplified by in vitro and in vivo models showing that inhibition of NF-kappaB sensitizes cancer cells to the effects of these drugs. New approaches focusing on the inhibition of NF-kappaB could help to minimize or even eliminate intrinsic or acquired resistance to platinum drugs.Metal-Based Drugs 02/2008; 2008:576104. DOI:10.1155/2008/576104
- [Show abstract] [Hide abstract]
ABSTRACT: Eulophia nuda L. (Orchidaceae) is a medicinally important terrestrial orchid used for the treatment of tumours and various health problems by the local healers throughout the Western Ghats region in Maharashtra (India). To isolate the active molecule from Eulophia nuda and to study its cytotoxic potential against human cancer cells. The crude methanolic extract of Eulophia nuda tubers was fractionated by stepwise gradient of the solvents-chloroform-methanol to isolate the pure compound. Isolated pure compound was assessed for its cytotoxic potential against human breast cancer cell lines, MCF-7 and MDA-MB-231 using MTT assay. Structure elucidation of the isolated active compound was carried out by extensive spectroscopic analysis including (1)H NMR, (13)C NMR, NOESY, COSY, LC-MS and IR. The isolated active molecule was identified as phenanthrene derivative 9,10-dihydro-2,5-dimethoxyphenanthrene-1,7-diol. This compound showed good antiproliferative activity against human breast cancer cell lines MCF-7 (91%) and MDA-MB-231 (85%) at 1000 microg/ml concentration. 9,10-Dihydro-2,5-dimethoxyphenanthrene-1,7-diol from Eulophia nuda tubers showed good growth suppressive effect against human cancer cell lines MCF-7 and MDA-MB-231 making it a potential biomolecule against human cancer.Journal of ethnopharmacology 03/2010; 128(1):251-3. DOI:10.1016/j.jep.2009.12.031 · 2.94 Impact Factor