Plant extracts have traditionally been used as aphrodisiacs and a recent report describes the synthesis of a modified natural product that could be as effective as sildenafil (Viagra®) for treating erectile dysfunction. Icariin, a component of Epimedium brevicornum (also known as horny goat weed) was found to inhibit phosphodiestersae-5 (PDE5), but with an IC50 value almost 100-fold greater than that of sildenafil.
The researchers then modified the structure of icariin to produce compound 5 which was essentially equipotent with sildenafil as an inhibitor of PDE5. Since compound 5 is more selective for PDE5 than sildenafil, which also inhibits phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE), compound 5 has the potential to cause fewer side effects than sildenafil.
Author: SR
New Mechanism for Treatment of Tumours
More than 80 years ago, Nobel laureate Otto Heinrich Warburg pointed to a difference in mitochondrial energy metabolism between tumour cells and normal healthy cells. This observation led to significant advances in cancer imaging using positron emission tomography (PET) and, because the altered energy metabolism is common to many types of cancer cells but not normal cells, it is also an attractive target for therapy. Now, Cornerstone Pharmaceuticals has announced the start of a clinical trial with a ‘thioctan’, CPI-613, the first example of an altered energy metabolism-directed (AEMD) compound.
In laboratory tumour models and animal studies, the new class of compounds were effective, even against difficult to treat tumours such as those of the lung, colon and pancreas, and showed very few adverse effects.
The AEMD technology platform being developed by Cornerstone is based upon the research of Paul M. Bingham, Ph.D. and Zuzana Zachar, Ph.D., Stony Brook University, Stony Brook, NY. These scientists disclosed ‘Lipoic acid derivatives and their use in treatment of disease’ in a patent filed in 1999.
The inventors describe key differences between metabolism in normal cells compared to that in cancerous cells:
The vast majority of normal cells utilize a single metabolic pathway to metabolize their food. The first step in this metabolic pathway is the partial degradation of glucose molecules to pyruvate in a process known as glycolysis or glycolytic cycle. The pyruvate is further degraded in the mitochondrion by a process known as the tricarboxylic acid (TCA) cycle to water and carbon dioxide, which is then eliminated. The critical link between these two processes is a large multi-subunit enzyme complex known as the pyruvate dehydrogenase (“PDH”) complex (“PDC”). PDC functions as a catalyst which funnels the pyruvate from the glycolytic cycle to the TCA cycle.
Most cancers display profound perturbation of energy metabolism. This change in energy metabolism represents one of the most robust and well-documented correlates of malignant transformation.
Because tumor cells degrade glucose largely glycolytically, i.e. without the TCA cycle, large amounts of pyruvate must be disposed of in several alternate ways. One major pathway used for disposal of excess pyruvate involves the joining of two pyruvate molecules to form the neutral compound acetoin. This generation of acetoin is catalyzed by a tumor-specific form of PDC. Although the TCA cycle still functions in cancer cells, the tumor cell TCA cycle is a variant cycle which depends on glutamine as the primary energy source. Tumor-specific PDC plays a regulatory role in this variant TCA cycle. Thus, inhibition or inactivation of a single enzyme, namely tumor-specific PDC, can block large scale generation of ATP and reducing potential in tumor cells.
Less Protein for a Longer Life?
Starting in the 1930s, a number of studies in laboratory animals have concluded that a reduced calorie diet, which delivers sufficient vital nutrients, results in a longer life and delays age-related diseases. Because of these findings in animals, many people have voluntarily adopted calorie-reduced diets in the hope of increasing longevity and improving health.
A new study has shown, however, that a nutritious low calorie diet may be less effective at prolonging life in humans. In many species, reduced function mutations in the insulin / insulin-like growth factor 1 (IGF-1) signalling pathway increase maximal healthy lifespan. Although calorie restriction in rodents decreases serum concentrations of IGF-1 by around 40%, with an accompanying beneficial effect on life span, the long term effects of calorie restriction on circulating IGF-1 levels in humans was not known.
The new study has shown that, in humans, long term calorie restriction with adequate nutrients does not lead to similar changes in IGF-1 levels. By contrast, reduced protein intake did lead to a significant reduction in circulating IGF-1. These data suggest that reduced protein intake rather than just reduced calorie intake may be important to improve health and delay ageing in humans.
Malaria Uses Cholesterol Receptor to Enter Liver Cells
Malaria is a global health problem and causes 2 – 3 million deaths each year. Mosquito bites allow malaria parasites to enter the bloodstream. Within 30 minutes, the parasites are transported to the liver where they enter cells and start to reproduce rapidly. Following release from hepatocytes, the parasites re-enter the bloodstream and infect red blood cells, triggering the pathology that is associated with malaria.
The receptor on human liver cells that allows the malaria parasites to enter hepatocytes has been identified as the scavenger receptor (SR-B1). This receptor normally transfers cholesteryl esters and other lipids from high density lipoprotein (HDL) in the bloodstream into liver cells. A new study shows that, in cell culture experiments as well as experiments in mice, blocking the SR-B1 receptor dramatically reduced the ability of the malaria parasite to infect liver cells. The researchers used RNA interference (RNAi), monoclonal antibodies, and small molecule inhibitors to demonstrate the importance of the SR-B1 receptor for entry of malaria parasites into hepatocytes. The study demonstrates that blocking the SR-B1 receptor may offer a new approach to the prophylaxis of malaria.
Targeting host mechanisms promises better protection against the emergence of resistant strains of the malaria parasite but, in this case, should be balanced against the atherosclerotic potential of long term blockade of the SR-B1 receptor.
PKC Inhibitor: New Option for Treatment of Psoriasis
The precise cause of psoriasis is not known but a number of factors, such as skin injury and infection, are thought to trigger outbreaks. T-cells become activated, leading to an acceleration of the normal replacement processes of the skin and an accumulation of skin cells as plaques on the surface of the skin. First line treatments include emollients and topical application of drugs such as vitamin D derivatives, coal tar preparations, steroids, vitamin A derivatives and dithranol. For refractory cases, retinoids or immunosuppressants may be prescribed. A recent study shows that the selective PKC inhibitor, AEB071, may become a new therapeutic option for the treatment of psoriasis. At a dose of 300 mg bid, AEB071 was well tolerated and improved the symptoms of psoriasis within a 2-week treatment period.
AEB071 is also undergoing clinical trials in kidney and liver transplant patients.
New Drugs Could Make Tumour Cells More Sensitive to Radiotherapy
In the rare inherited human disease, ataxia-telangiectasia (A-T), a mutation is present in a gene encoding a protein that normally activates cellular responses to DNA damage. The mutation in the ATM gene leads to decreased ability to repair damaged DNA, and an increased sensitivity to ionising radiation and other DNA damaging agents. This highlights the ATM pathway as a potential target to increase the sensitivity of tumour cells to radiotherapy or chemotherapy. The ATM protein demonstrates kinase activity and a selective, small molecule inhibitor of this kinase, CP466722, has now been shown to enhance the sensitivity of tumour cells grown in vitro to ionising radiation.
Inhibition of ATM kinase activity is rapid, and is completely and rapidly reversed on wash-out; further experiments suggested that inhibition of ATM for a short period of time may be sufficient to sensitise tumour cell to radiotherapy. Because CP466722 is effective in murine cells as well as human cells, it may be possible to use mouse models to further explore the potential of using ATM inhibitors to increase the effectiveness of radiotherapy.
New Drug May Prevent Multiple Sclerosis
Multiple sclerosis (MS) is a disorder of the central nervous system with initial inflammation of the protective myelin sheath encasing nerve fibres. Symptoms vary widely and often occur initially as discrete episodes interspersed with relatively symptom-free periods (relapsing MS).
A drug currently being tested for its effectiveness in treating relapsing forms of MS is now to be tested to see whether it can prevent the disease from developing. The drug, cladribine, will be given orally to patients who have a first clinical event suggestive of MS. Patients will be treated for two years, or up to the time when they experience a second attack leading to a definite clinical diagnosis of MS. Treatment will be given in two or four cycles in the first year, with a single daily dose of cladribine tablets being given on four to five consecutive days in each cycle. This means that patients in the study will take cladribine for only 8 – 20 days in the first year. In the second year, two treatment cycles will be given to all patients.
Cladribine is also used as an intravenous infusion to treat hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin’s lymphomas.
Botox Shown to Work for Chronic Migraines
Migraine is very prevalent worldwide. Attacks are more common in women and can occur at any age, but often diminish after the age of 50. Migraine pain is usually described as a severe throbbing or pulsating headache, often with nausea and sensitivity to light, which can last for many hours or even days.
The benefits of Botulinum Toxin (Botox®) in migraine were discovered accidentally when injections to reduce lines and wrinkles were reported to reduce the frequency and severity of headaches. Top-line analyses of data from two Phase III clinic trials confirm that Botox® is effective for the prophylaxis of chronic migraine. Patients were given Boxtox® or placebo injections every 12 weeks, and the primary analysis was carried out after two treatment cycles. The efficacy measures were the change in number of headache episodes and headache days compared with the 28 days preceding treatment. One study showed no significant reduction in the number of headache episodes between patients receiving Botox® and placebo, but a significant reduction in the number of headache days in the treatment group. The second study showed a benefit in terms of both number of headache episodes and headache days for the Botox® treated group. In both studies, patients receiving Botox® treatment reported significantly improved quality of life compared with patients receiving placebo.
New DPP-4 Inhibitor Demonstrates Glucose Control in Type 2 Diabetes
Type-2 diabetes is a metabolic disorder that is increasing rapidly in the developed world. The disease is caused by reduced production of insulin by the pancreas and /or reduced responsiveness to insulin by cells in the body, particularly fat, muscle and liver cells. Reduced insulin activity causes higher blood glucose levels as well as other complex metabolic changes, leading eventually to organ damage with increased morbidity and mortality.
A number of medicines are used to treat type-2 diabetes; these include metformin, sulphonyl ureas, and thiazolidinediones. More recently, inhibitors of dipeptidyl peptidase-4 (DPP-4) have emerged as an alternative method of treatment. DPP-4 inhibitors act by increasing levels of the gastrointestinal hormones, incretins, which increase the amount of insulin released by the pancreas, inhibit glucagon release and also slow gastric emptying.
New data has been presented showing that Januvia™ (sitagliptin), in combination with metformin, provided significant glucose lowering over two years. In separate studies, addition of Januvia™ to regimens based on thiazolidinediones also led to improved blood sugar control. Januvia™ was the first DPP-4 inhibitor to be approved for the treatment of diabetes in the US and Europe although several other inhibitors are in varying stages of development.
Small Molecules Lend a Hand in Protein Folding
Protein folding is the process whereby newly synthesised linear polypeptide chains fold into the well-defined 3-dimensional shape of the functional protein. In many cases, molecular chaperones assist in correct protein folding by preventing the newly synthesised protein from aggregating into non-functional structures. A variety of diseases result from misfolded proteins; loss-of-function diseases are often caused by a point mutation in the sequence of the protein which disturbs the normal balance between protein folding and clearance. There has been recent interest in the development of ‘pharmacological chaperones’ which are small molecules that stabilise the correct protein fold.
A recent study describes two small molecules, celastrol and MG-132, that are able to enhance mutant protein folding and function in cell culture experiments. These compounds acted synergistically with known pharmacological chaperones and increased the activity of mutant proteins to 50% of wild-type activity. This study provides encouragement for the concept of developing regulators of proteostatis for the treatment of a range of loss-of-function diseases.