Metabolomics Approaches Shine New Light on Diabetes Mechanisms
New study links elevated levels of lipid metabolite to gestational and Type 2 diabetes
Collaborating researchers from Canada, the USA and China, have discovered that patients with gestational diabetes mellitus (GDM) or Type 2 diabetes (T2DM) demonstrate elevated plasma levels of furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), potentially paving the way for new approaches for treating the disease.
The team analyzed the blood of GDM and T2DM patients and identified differences in a number of metabolites present compared with normal glucose tolerance controls. In addition, diabetes patients showed elevated levels of CMPF.
The team went on to show that CMPF enters β cells through organic anion transporter 3 (OAT3), and at high concentrations causes β cell dysfunction through impairment of mitochondrial function and inhibition of insulin biosynthesis. Interestingly, the effects of CMPF could be prevented through blocking the transport of CMPF intracellularly or treatment with antioxidants.
When discussing the implications this work might hold for future therapeutic development, Michael Wheeler, senior author of the study, commented “There are three main possibilities. First, CMPF transport blockade and antioxidant treatment may be possible treatments of T2DM. Second, CMPF may act as a predictive biomarker of GDM and T2DM. Third, CMPF may act as a companion diagnostic for the assessment of β cell function and drug interventions in T2DM. Any of these three possibilities would have a major impact on diagnosis and treatment of diabetes.”
Potential future applications will include determining whether CMPF can act as a predictive biomarker of GDM and T2DM. According to Wheeler, “We plan to screen larger cohorts of patients at high risk of developing T2DM as well as following women who had GDM postpartum. In addition, we would like to determine the ability of CMPF to act as a companion diagnostic for the assessment of β cell function and drug interventions in T2DM. Initial studies have been planned to measure CMPF in subjects on different antidiabetic medications”.
The team also plan to examine CMPF transport blockade and antioxidant treatment as possible treatments of T2DM. OAT transporters have been identified as potential targets and studies are planned to determine in models of T2DM if OAT blockers as well as antioxidants can prevent CMPF-induced glucose intolerance and reverse diabetes.
– Written by Evgenia Koutsouki
Source: Prentice KJ, Luu L, Allister EM et al. The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. Cell Metab. 19(4) 653–666 (2014).
Surface Receptor Cd44: A Potential Target in the Fight Against Pancreatic Cancer?
Researchers from China and the USA have discovered that targeting the surface receptor CD44s can block pancreatic tumor formation and prevent its recurrence after radiotherapy.
The team measured levels of CD44s receptor in pancreatic cancer tissues and in adjacent nontumor tissues from pancreatic cancer patients. They discovered that patients whose tumors expressed high levels of CD44s had a significantly lower survival time than patients with tumors expressing low levels of CD44s. Using an antibody targeting CD44s in mice with human pancreatic tumor xenografts, the team found that anti-CD44s reduced tumor growth and metastasis, as well as recurrence following radiotherapy. The antibody also reduced the number of tumor initiating cells in cultured pancreatic cancer cells, and inhibited cell proliferation and survival signalling.
Speaking to Future Medicinal Chemistry, Liang Xu, the senior author of the study commented: “Our results support the current hypothesis that cancer stem cells promote radiation resistance and tumor recurrence, and provide proof-of-concept for using anti-CD44 antibody to overcome radiation resistance and tumor recurrence. This is a whole new strategy for molecular therapy targeting cancer stem cells.”
Pancreatic cancer is a serious form of cancer for which diagnosis and treatment are particularly difficult. When discussing future research projects, Xu commented: “Based on this proof-on-concept study, we are currently studying the humanized anti-CD44 antibody, and plan for future clinical trials to test this novel strategy to overcome radiation resistance and tumor recurrence.”
– Written by Evgenia Koutsouki
Source: Li L, Hao X, Qin J et al. Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice. Gastroenterology 146(4) 1108–1118 (2014).
Cancer Cell Survival Mechanisms: A Potential Target for Cancer Therapy?
A group of researchers from Sweden has identified another example of the non-oncogene addiction concept for cancer treatment. The method is based on targeting MTH1, an enzyme required for cancer cell survival.
MTH1 acts by inhibiting incorporation of oxidized nucleotides into the DNA strand during replication. The research team demonstrated that lack of MTH1 leads to cancer cell death due to DNA damage. They also identified small molecules that are able to inhibit MTH1 action in cells by binding the active site of the enzyme. In vivo studies showed that use of these inhibitors in patient-derived mouse xenografts result in incorporation of oxidized dNTPs in cancer cells that subsequently lead to DNA damage, cytotoxicity and therapeutic responses. This strategy may be potentially effective in all types of cancer as the team showed that all tested types of cancer cells need MTH1 for cell survival.
When discussing the significance of these results, Thomas Helleday, senior author of the study commented: “We have found an enzymatic activity critical for cancer cell survival and not required for normal cells – demonstrating a new concept of ‘cancer phenotypic lethality’ to treat cancer.”
The non-oncogene addiction concept for anticancer treatment is based on the fact that processes required for tumor survival are not directly responsible for cancer formation. Since the action of MTH1 is required for survival by all cancer cells irrespective of the mutations found in specific cancers, this could mean that problems of resistance that are usually encountered during chemotherapy might be avoided in this case.
“We think this can be a maintenance treatment for most cancers, providing the drug off-target effects are not producing delibitating side effects” says Helleday. When discussing future plans Helleday commented “We send out the compound worldwide to hopefully get as many scientists as possible to explore their own ideas of how to use it.”
– Written by Evgenia Koutsouki
Source: Gad H, Koolmeister T, Jemth A et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature 508, 215–221 (2014).
Rapid Synthesis of Peptide Drugs Holds Promise for Improved Drug Development
Peptide drugs hold promise for the treatment of a number of diseases; however, currently a bottleneck in manufacturing of these drugs is holding back these potential therapies. Researchers at Massachusetts Institute of Technology (MA, USA) have found a way to potentially overcome this bottleneck, by developing a method that could manufacture peptides in hours instead of the current timeframe of several weeks.
Bradley Pentelute, leader of the research group commented, “Peptides are ubiquitous. They’re used in therapeutics, they’re found in hydrogels, and they’re used to control drug delivery. They’re also used as biological probes to image cancer and to study processes inside cells. Because you can get these really fast now, you can start to do things you couldn’t do before.”
The new method can assemble a peptide in less than an hour, the machine has a storage vessel for each of the 20 naturally occurring amino acids, and the vessels are connected to a pump that selects the correct one. The amino acids travel through a heated coil on the way to the reaction chamber, this step speeds up the synthesis reactions, which have now been adapted so that they can becarried out in a continuous flow system. The purity of these peptides is as pure as those produced using the traditional methods. Pentelute explains, “We’re on par with the world’s best state-of-the-art synthesis, but we can do it much faster now.”
The technology would mean that peptides could be rapidly designed and tested for the treatment of cancer and other diseases, and potential synthesis problems could be detected and fixed much faster than with the current methods. Pentelute believes that in future versions, “We think we’re going to be able to do each step in under 30 seconds. What that means is you’re really going to be able to do anything you want in short periods of time.”
– Written by Lisa Parks
Sources: Fast synthesis could boost drug development: http://newsoffice.mit.edu/2014/fast-synthesis-could-boost-drug-development; Simon M, Heider P, Adamo A et al. Rapid flow-based peptide synthesis. Chembiochem 15(5), 713–720 (2014).
Cocrystals Help to See Improved Therapeutic Action for Eye Disease
Cocrystallization of a popular antibiotic, currently used for the treatment of ocular infections, with caffeine has been found to improve resistance of the drug to blinking. Sulfacetamide (SACT), when applied as a treatment for conjunctivitis or other ocular problems, is quite often lost on blinking, therefore reducing its concentration at the site and in turn reducing its therapeutic efficiency, necessitating larger and more frequent doses of the antibiotic.
A team of scientists based at the University of Hyderabad in India has managed to solve this problem through cocrystals. The researchers decided to replace weak hydrogen bonds with stronger bonds to lower the solubility and dissolution rate. SACT was cocrystallized with a number of molecules including caffeine, isonicotinamide, theophylline, bipyridine and a salt with 4-aminopyridine.
After thermal, spectroscopic and diffraction characterization techniques, it was discovered that caffeine was the most suitable; the drug was less soluble and formed denser crystals and packing, compared with SACT alone. As suspected, the cocrystal included stronger N–H‐‐‐O bonds compared with previous C–H–O bonds in the drug alone, therefore causing tighter crystal packing and lower solubility.
– Written by Lisa Parks
Source: Nangia A, Goud R, Khan RA. Modulating the solubility of sulfacetamide by means of cocrystals. CrystEngComm. doi:10.1039/C4CE00103F (2014) (Epub ahead of print).