Cucurbitacin D induces fetal hemoglobin synthesis in K562 cells and human hematopoietic progenitors through activation of p38 pathway and stabilization of the γ-globin mRNA.

The search for novel therapeutic candidates targeting fetal hemoglobin (HbF) activation to reduce the imbalance of globin genes is regarded as a promising approach for the clinical management of sickle cell disease and ß-thalassemia. For the first time, we identified cucurbitacin D (CuD), an oxygenated tetracyclic triterpenoid, as a molecular entity inducing γ-globin gene expression and HbF synthesis in K562 cells and human hematopoietic progenitors from a ß-thalassemia patient. CuD demonstrated a higher potency in HbF induction when compared with hydroxyurea, which was revealed by the evidence that CuD results in a higher fetal cell percentage and greater HbF content in K562 cells, in addition, to being less cytotoxic. Moreover, CuD also promotes higher HbF expression in primary erythroid cells. In the study to elucidate the molecular mechanisms of CuD's action, our data indicated that CuD-stimulated HbF synthesis was mediated by p38 pathway activation. At the post-transcriptional level, CuD treatment led to a significant elongation of the γ-globin mRNA half-life in K562 cells. Taken together, the results suggest that CuD may be a potential therapeutic agent for ß-hemoglobinopathies, including sickle cell anemia and ß-thalassemia.

Microsomal glutathione S-transferase gene polymorphisms and colorectal cancer risk in a Han Chinese population.

BACKGROUND AND AIMS: Glutathione S-transferases (GSTs) are phase II detoxification enzymes. Human GSTs have been classified into cytosolic, mitochondrial, and microsomal families. Several studies reported the association of colorectal cancer (CRC) risk with the genetic polymorphisms of cytosolic GSTs. The microsomal GSTs are structurally distinct but functionally similar to cytosolic GSTs; their association with CRC has not been reported. In this report, we summarized the result of a case-control study aimed at investigating the association of MGST1 gene locus polymorphisms with CRC risk among Han Chinese. PATIENT/METHODS: Three hundred and seventy-two healthy controls and 238 sporadic CRC patients participated in this study. DNA resequencing was conducted for the 3.4 kb genomic DNA region containing the promoter, exons, exon-intron junctions, and the 5' and 3' untranslated regions. RESULTS: We detected 13 single nucleotide polymorphisms (SNPs) including four novel SNPs not reported in database/literature. The gene shows a much higher nucleotide diversity than most human genes. The linkage and recombination analysis revealed 24 common haplotypes (13% > or = freq > or = 1%) and identified extensive intragenic recombination throughout the MGST1 locus (R = 81.8). Significant CRC association (P < or = 0.005) was not detected for each individual SNP. However, SNPs 102G>A and 16416G>A reached a marginal level of statistical significance with P values of 0.016 and 0.078, respectively. A combined genotype analysis detected a statistically significant CRC association for individuals carrying 102G>A/16416G>A (GG/GG) genotype (adjusted OR, 1.682; 95% confidence interval (CI), 1.177-2.404; P = 0.004). Consistent with the results of genotype analysis, the GG haplotype (102G>A/16416G>A) with two risk alleles was associated with a significantly higher CRC risk comparing with the haplotypes with one or no risk allele (adjusted OR 1.744; 95% CI 1.309-2.322; P = 0.0001). CONCLUSION: The results suggest that MGST1 polymorphisms may contribute to CRC risk among Han Chinese.