Epothilone Therapeutics (Abraxis/Scripps Research Institute)

Natural products and their derivatives have played a dominant role in the development of therapeutic agents. Traditionally, most of the natural products developed for the effective treatment of different diseases have been sourced from plants. Natural product discovery has seen a shift of focus towards microorganisms due to the chemical diversity of bioactive products they synthesize. Myxobacteria produce a large variety of novel chemical entities with diverse structures and varied bioactivities. In the last few decades, secondary metabolites from different genera of myxobacteria have been recognized as harbouring potent anticancer activity. Several analogs of these anticancer compounds have been prepared to address the limitations such as, poor solubility, high toxicity and low production yield, in order to obtain the compounds in higher quantities with better pharmacological properties and target selectivity. For example, a semi-synthetic derivative of epothilone obtained from a strain of myxobacterium has been approved for clinical use against taxane-resistant breast cancer. The anticancer compounds from myxobacteria target microtubules, the cytoskeleton, vacuolar ATPase, methionine aminopeptidase, exportin, the proteasome or translation elongation factor to exert anticancer activity. The focus of this review is on the promising anticancer compounds produced by myxobacteria, their targets and their mechanisms of action in cancer cells.

Rehabilitation is widely recognized as an essential component in evaluating the effectiveness of a therapeutic intervention in animal models of translational spinal cord injury research. Ideally, the rehabilitation method used should be optimized for the specific injury model and severity to adequately compare the efficacy of the investigational therapy. For studies utilizing thoracic spinal cord injuries, rehabilitation primarily involves bipedal or quadrupedal treadmill training aimed at restoring hindlimb function. Previously, we reported modest improvements to hindlimb motor recovery following forced bipedal treadmill training after moderate 175 kilodyne thoracic spinal cord contusion injury, which were further enhanced when combined with the microtubule-stabilizing drug epothilone B. However, during this and other studies we have noted that B-TMT presents several potential limitations, including brief periods of active rehabilitation for each animal, variability between animal handlers, animal stress, and the focus on a single movement pattern. To overcome these limitations, we investigated the effects of an environmental enrichment-based rehabilitation that differs from a general environment enrichment strategy by including task-specific training elements, something we have termed ‘targeted environmental enrichment’. This method provides longer periods of active rehabilitation, operates independently of the animal handler, thereby involves less animal handling, which minimizes stress, and encourages a wide range of movements. Our findings indicate that targeted environmental enrichment outperforms bipedal training across several behavioural measures which produced a ceiling effect that epothilone B could not overcome. Therefore, these results suggest that targeted environmental enrichment may be a more effective rehabilitation approach than B-TMT and should be considered for application in models of severe spinal cord injury.