Drug Discovery Opinion

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.

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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.

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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.

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