9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor currently being developed as an antineoplastic agent. The aim of these preclinical studies was to assess the activity of 9-AC against prostate cancer, a malignancy notoriously insensitive to most cytotoxic agents in the clinic. The activity of 9-AC was first tested in vitro against one hormone-sensitive (LNCaP) and three hormone-resistant (PC-3, PC-3M, and DU145) human prostate cancer cell lines. After 96 h of drug exposure, concentrations required to inhibit cell viability to 50% of control values (IC50s) were 34.1, 10, 6.5, and 8.9 nm for PC-3, PC-3M, DU145, and LNCaP, respectively. Because 9-AC is known to undergo rapid hydrolysis, we assayed lactone levels in tissue culture medium over 24 h and found that the half-life was 20 min, with only 15%of the drug remaining as lactone at steady state. Consequently, the IC50s calculated from a single dose of the drug may represent overestimates. Subsequently, we tested the activity of a colloidal dispersion formulation of 9-AC against PC-3 implanted into flanks of nude mice. 9-AC was given for a total of 3 weeks by daily oral gavage (excluding weekends) or by twice weekly s.c. injections. 9-AC inhibited tumor growth at the lowest oral dose (0.35 mg/kg/day), whereas higher oral doses (0.75 and 1 mg/kg/day) and s.c. administration (4 mg/kg/week) caused tumor regression. 9-AC was well tolerated at all doses, with no toxic death or weight loss of more than 10% observed in any group. Finally, we considered that the activity of 9-AC seen in the mouse xenograft model might be explained, in part, by the relatively acidic tumor microenvironment, which would favor the formation of the more potent lactone. Simultaneous determination of plasma and tumor 9-AC lactone concentrations confirmed this hypothesis. Taken together, these studies suggest that 9-AC should be submitted for clinical trials in patients with prostate cancer.

BMC Molecular and Cell Biology

Evaluation of antibacterial and anticancer properties of secondary metabolites isolated from soil Bacillus spp focusing on two strains of Bacillus licheniformis and Bacillus siamensis

Article

作者: Bamzadeh, Zahra ; Shahniani, Ahmadreza ; Mahmoudnia, Fahimeh ; Rouhi, Leila

BACKGROUNDBacillus strains are well recognized for their inherent production of bioactive compounds that exhibit antibacterial and anticancer properties. This study aims to evaluate the antimicrobial and anticancer effects of the secondary metabolite isolated from Bacillus licheniformis and Bacillus siamensis strain.MATERIAL AND METHODWe developed and purified a new soil-derived Bacillus strain to study its metabolites on cancer cells and bacteria. After evaluating the antimicrobial effects of the selected strains' secondary metabolites by well diffusion, growth conditions and temperature optimised using liquid-liquid extraction, secondary metabolites isolated, and active compounds identified using GC-MS. Evaluation of PC-3 and HPrEpC cytotoxicity. AV/PI staining and comet assay assessed necrosis and apoptosis. Real-time PCR measured apoptotic gene expression. Finally, the scratch test measured cell movement.RESULTSBacillus strain metabolites exhibit dual-purpose antimicrobial and anticancer properties. Bacillus licheniformis isolate 56 and S2-G12 isolate 60 demonstrated the greatest antibacterial activity. Among all Bacillus isolates, isolates 56 (Bacillus licheniformis) and 60 (Bacillus siamensis strain) had the highest antibacterial activity. Crude extracts obtained from strains 56 and 60 decreased PC-3 cell viability in a dose-dependent manner. At 200 µg/mL, the survival rate of cells treated with strain 56 and 60 crude extract was 23% and 25%, respectively (p < 0.001). The treatment of PC-3 cells with strains 56 and 60 crude extract led to considerable apoptosis (46.2% and 50.09%, respectively) compared to the control group. After treatment with the crude extract from strains 56 and 60 at an IC₅₀ concentration, a significant number of PC-3 cells showed comet formation, indicating DNA fragmentation. Metabolites extracted from strain 56 and 60 enhanced caspase 3, caspase 8, and Bax genes expression and reduced Bcl-2 expression (p < 0.001). Cell migration was also prevented.CONCLUSIONOur findings show that the secondary metabolites of B. licheniformis and B. siamensis have antibiotic and anticancer properties. However in vivo studies are necessary to confirm these findings.

Medeniyet Medical Journal

The Anti-proliferative Effect of a Novel Glutaminase Inhibitor IN-3 on Prostate Cancer Cells

Article

作者: Celik, Ayse Busranur ; Demir, Ummuhan ; CELIK, Ayse Busranur ; DEMIR, Ummuhan

ObjectiveThis study aimed to evaluate anti-cancer potential of a novel glutaminase (GLS) inhibitor IN-3 in prostate cancer cells.MethodsThe cell viability upon IN-3 treatment was examined using crystal violet staining and IC₅₀ values were calculated for cancer cell lines PC-3 and LNCaP and normal fibroblasts CCD1072sk. The expression levels of GLS isoforms were determined by real-time polymerase chain reaction after IN-3 treatment. The metastatic prostate cancer dataset was downloaded from C-Bioportal and the expressions of GLS isoforms were analyzed.ResultsThe IC₅₀ values of IN-3 for LNCaP, PC-3 and CCD1072sk were 2.13, 6.14 and 15.39 μM respectively. The dose dependent effect of IN-3 was evident even in low concentration with 1 μM in LNCaP and 2 μM in PC-3 and these anti-proliferative effects of IN-3 were highly significant with p-values lower than 0.0001. The treatment of PC-3 cells with 10 μM IN-3 elevated the expression of kidney type GLS isoform of GLS1 but not GLS2. Comparison of metastatic and localized prostate cancer tissues showed that GLS1 was highly expressed not only in primary but also in metastatic prostate cancer tissues. GLS1 expression was significantly higher than GLS2 expression with p-values lower than 0.001.ConclusionsThe GLS inhibitor IN-3 may be a potent anti-cancer agent in prostate cancer by demonstrating its differential effect between cancer and normal cells. Further studies are warranted to elucidate its drug potential in prostate cancer.

100 项与 PC-0003 相关的药物交易

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