Search

Fifteen aromatic analogues of conduritol F., L-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters are synthesized and evaluated for anticancer activity. The analysis of the compounds reveal that they possess four of the six pancratistatin stereocenters and serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry.

Introduction: Cancer stem cells (CSCs) possess characteristics associated with normal stem cells, specifically the abilities to renew themselves and to give rise to all cell types (differentiation). It is assumed that induction of differentiation in CSCs would reduce their ability to form tumors. What triggers CSC differentiation and the role of "differentiation" in tumorigenesis remain elusive. Methods: Glioma stem cell (GSC) lines and subcutaneous as well as orthotopic xenografts established from fresh surgical specimens of glioblastoma multiforme were used. Results: Exposure of GSCs to serum activates mitochondrial respiration and causes an increase in mitochondrial reactive oxygen species (ROS) as well as oxidative stress responses, leading to the appearance of differentiation morphology and a deceased expression of CSC markers. Chemical perturbation of the mitochondrial electron transport chain causes ROS increase and further downregulation of stem cell markers, while antioxidant N-acetylcysteine reduces ROS and suppresses the differentiation of GSCs. Surprisingly, the serum-induced differentiated GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by N-acetyl-cysteine. Mitochondrial ROS from the serum-stimulated cells triggered the activation of nuclear factor-kappa-B (NFκB) pathway, which is a potential mechanism for the promotion of tumorigenesis. Conclusion: This study suggests that ROS generated from active mitochondrial respiration in the presence of serum is critical in CSCs activation, which promotes tumor development in vivo. [ABSTRACT FROM AUTHOR]

Increased aerobic glycolysis and oxidative stress are important features of cancer cell metabolism, but the underlying biochemical and molecular mechanisms remain elusive. Using a tetracycline inducible model, we show that activation of K-rasG12V causes mitochondrial dysfunction, leading to decreased respiration, elevated glycolysis, and increased generation of reactive oxygen species. The K-RAS protein is associated with mitochondria, and induces a rapid suppression of respiratory chain complex-I and a decrease in mitochondrial transmembrane potential by affecting the cyclosporin-sensitive permeability transition pore. Furthermore, pre-induction of K-rasG12V expression in vitro to allow metabolic adaptation to high glycolytic metabolism enhances the ability of the transformed cells to form tumor in vivo. Our study suggests that induction of mitochondrial dysfunction is an important mechanism by which K-rasG12V causes metabolic changes and ROS stress in cancer cells, and promotes tumor development. [ABSTRACT FROM AUTHOR]

It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.