Objective:This study investigated the expression of MAPK-activating death domaincontaining protein (MADD) in lung adenocarcinoma and its impact on lung adenocarcinoma SPCA- 1 cell proliferation and apoptosis.Methods:Clinicopathological lung specimens were collected. MADD expression levels in normal human lung and human lung adenocarcinoma tissues were detected by immunohistochemistry. Lung adenocarcinoma SPC-A-1 cells were cultured, and IG20 gene expression in the SPC-A-1 cells was detected using reverse-transcription PCR. SPC-A-1 cells were transfected with a plasmid carrying the MADD gene and a lentiviral vector capable of silencing MADD expression. CCK-8 assay, western blot and flow cytometry were performed to detect MADD expression, proliferation and apoptosis in the SPC-A-1 cells.Results:MADD expression levels in the lung adenocarcinoma tissue were significantly higher than those in the normal lung tissue and lung squamous carcinoma cells. MADD can be expressed in lung adenocarcinoma SPC-A-1 cells. High MADD expression can inhibit SPC-A-1 cell apoptosis and enhance SPC-A-1 cell proliferative activity, while silencing MADD expression can promote apoptosis and reduce SPC-A-1 cell proliferation.Conclusion:MADD expression is significantly upregulated in lung adenocarcinoma tissue. MADD can promote lung adenocarcinoma cell growth by inhibiting apoptosis. This study may improve lung adenocarcinoma levels in patients and, thus, is worthy of clinical promotion.

2009-10-01·European Journal of Clinical Pharmacology3区 · 医学

Pharmacokinetics of chlorproguanil, dapsone, artesunate and their major metabolites in patients during treatment of acute uncomplicated Plasmodium falciparum malaria

3区 · 医学

Article

作者: Ann K. Miller ; Nibedita Bandyopadhyay ; Paula L. Kirby ; Stephen A. Ward ; Stephan Duparc ; Peter A. Winstanley ; Daniel G. Wootton

OBJECTIVEChlorproguanil (CPG)-dapsone (DDS)-artesunate was in development for the treatment of uncomplicated Plasmodium falciparum malaria. The pharmacokinetics of CPG, DDS, artesunate and their metabolites chlorcycloguanil (CCG), monoacetyl dapsone (MADDS) and dihydroartemisinin (DHA) were investigated in patients with P. falciparum given CPG-DDS alone or plus artesunate.METHODSAdult patients from Malawi and The Gambia taking part in a phase II clinical trial were randomised to receive a 3-day treatment of CPG-DDS alone (2/2.5 mg/kg/day) or plus 1, 2 or 4 mg/kg/day artesunate. Blood samples for pharmacokinetic analysis were collected up to 24 h post-first dose.RESULTSThe pharmacokinetic analysis included 115 patients. For CPG, there was no significant effect of artesunate on C(max) or AUC(0-24), except the 90% confidence interval (CI) for AUC(0-24) for the 4 mg/kg artesunate dose was slightly below that for the standard bioequivalence range (90% CI 0.78, 1.11); this was not considered clinically relevant. Artesunate increased the CCG AUC(0-24) by 6-17% and C(max) by 0-16%. Artesunate had no significant effect on the rate or extent of absorption of DDS. For MADDS, artesunate increased the AUC(0-24) by 13-47% and C(max) by 8-45%. For 1, 2 and 4 mg/kg artesunate dosing, artesunate AUC(0-infinity) was 64.6, 151 and 400 ng.h/ml and C(max) 48.9, 106 and 224 ng/ml respectively; DHA AUC(0-infinity) was 538, 1,445 and 3,837 ng.h/ml and C(max) 228, 581 and 1,414 ng/ml respectively. Using a power model, the point estimates of slope were greater than 1 for artesunate AUC(0-t) by 16% and C(max) by 5% and for DHA by 39 and 21% respectively.CONCLUSIONArtesunate did not significantly affect CPG or DDS pharmacokinetics. For CCG and MADDS, small to moderate increases in exposure with artesunate dosing were observed. There was a greater than proportional increase in artesunate and DHA exposure with increasing artesunate dose. These effects are not considered to be clinically relevant. It should be noted that the CPG-DDS-artesunate programme has now been stopped following unacceptable haematological toxicity in patients with glucose-6-phosphate dehydrogenase deficiency during a phase III trial. In addition, the CPG-DDS combination has been withdrawn from clinical use.

2006-10-12·Oncogene1区 · 医学

MADD/DENN splice variant of the IG20 gene is necessary and sufficient for cancer cell survival

1区 · 医学

Article

作者: D C Mordi ; B S Prabhakar ; N Mulherkar ; M Ramaswamy

The IG20 gene is overexpressed in human tumors and cancer cell lines, and encodes at least four splice variants (SVs) namely, IG20pa, MADD, IG20-SV2 and DENN-SV. Earlier, gain-of-function studies showed that IG20-SVs can exhibit diverse functions and play a critical role in cell proliferation and apoptosis. Expression of exogenous IG20pa or DENN-SV rendered cells either susceptible or resistant to induced apoptosis, respectively, whereas MADD and IG20-SV2 had no apparent effect. In order to understand the contrasting effects of the IG20-SVs in a physiologically more relevant system, we expressed exon-specific small hairpin RNAs (shRNAs) to selectively knockdown specific IG20-SVs. Consistent with an earlier study, knockdown of all IG20-SVs resulted in spontaneous apoptosis of HeLa and PA-1 cells. In addition, we unambiguously demonstrated that knockdown of MADD can render cells susceptible to spontaneous apoptosis but had no discernible effect on cell proliferation, colony size or cell cycle progression. Moreover, expression of MADD alone, and not DENN-SV, in the absence of endogenous IG20-SVs was sufficient to prevent spontaneous apoptosis. Our results show the utility of shRNAs for selective knockdown of particular IG20-SVs and their potential therapeutic value in cancer. Further, they demonstrate that MADD alone is sufficient and necessary for cancer cell survival.

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