Inhibition of liver glutaminase activity by Diallyl disulfide in experimentally induced hepatoma in mice

Background: Cancer cells addiction to glutamine, an essential non-essential amino acid, has stirred up the interest in researchers across the globe. Increased glutamine metabolism (glutaminolysis) is a hallmark of cancer. Targeting glutaminolysis via glutaminase inhibition emerges as a promising strategy to disrupt cancer metabolism and tumor progression. Diallyl disulfide (DADS), a major organosulfur compound derived from garlic, is known for its anticancer properties. The mechanisms of action of DADS include activation of metabolic enzymes that detoxify carcinogens, suppression of the formation of DNA adducts, antioxidant effects, regulation of cell-cycle progression, induction of apoptosis, and inhibition of angiogenesis and metastasis. Aim: to assess the effect of diallyl disulfide on liver glutaminase activity in experimentally induced hepatoma in mice. Materials & Methods: Swiss albino male mice were divided into four groups - normal, control, preventive and curative groups. Hepatoma was induced by intraperitoneal injection of Ehrlich ascites carcinoma (EAC) cells. DADS (100 mg/kg body weight/mouse/day) was orally fed to protective and curative group mice for a stipulated time period. Mice of all the groups were sacrificed, and liver tissue glutaminase activity were measured. Results: The present study shows a significant decrease in glutaminase activity in protective (p >0.001) and curative groups (p >0.001) as compared to control group. Conclusion: DADS at the dosage employed shows inhibitory effects on liver glutaminase activity which may be attributed to anti-inflammatory properties of DADS, specifically in suppression of NF-kB signalling pathway.

The emerging role and targetability of the TCA cycle in cancer metabolism

The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

Reprogramming of energy metabolism in cancer / 肿瘤

Cancers acquire reprogramming of energy metabolism to balance energy production and their biosynthetic needs. The altered metabolism includes aerobic glycolysis, glutaminolysis, reverse Warburg effect and truncated tricarboxylic acid cycle. Cancer cells principally rely on aerobic glycolysis through mitochondrial dysfunction, changes of key metabolic players, hypoxic microenvironment, and genomic changes. Understanding the style and mechanisms of cancer energy metabolism may lead to development of new approaches to reverse metabolic reprogramming.

Advances in improving mammalian cells metabolism for recombinant protein production

Background: The production of recombinant proteins for therapeutic use represents a great impact on the biotechnology industry. In this context, established mammalian cell lines, especially CHO cells, have become a standard system for the production of such proteins. Their ability to properly configure and excrete proteins in functional form is an enormous advantage which should be contrasted with their inherent technological limitations. These cell systems exhibit a metabolic behaviour associated with elevated cell proliferation which involves a high consumption of glucose and glutamine, resulting in the rapid depletion of these nutrients in the medium and the accumulation of ammonium and lactate. Both phenomena contribute to the limitation of cell growth, the triggering of apoptotic processes and the loss of quality of the recombinant protein. Results: In this review, the use of alternative substrates and genetic modifications (host cell engineering) are analyzed as tools to overcome those limitations. In general, the results obtained are promising. However, metabolic and physiological phenomena involved in CHO cells are still barely understood. Thus, most of publications are focused on specific modifications rather than giving a systemic perspective. Conclusions: A deeper insight in the integrated understanding of metabolism and cell mechanisms is required in order to define complementary strategies at these two levels, so providing effective means to control nutrients consumption, reduce by-products and increase process productivity.