Autophagy is a catabolic trafficking pathway for bulk destruction via regulated lysosomal degradation. In doing so, the cell removes the non-functional organelles, recycles them and thus obtains much-needed nutrients. Autophagy takes place in all cell types and this precisely regulated process is crucial for maintaining homeostasis. However, in some cases, the process of autophagy can be also detrimental for the organism, since it is strongly associated with a variety of human diseases, such as cancer, nervous system diseases, cardiovascular diseases, etc. Moreover, pathogenic microbes can also affect the autophagy pathway and turn it to their advantage. Autophagy may therefore be useful in some cases but not in others. With various small molecules, including some active substances, we can modulate the process of autophagy, which can be exploited for therapeutic purposes. Many active substances, which primary indication is not action on the process of autophagy, show secondary pharmacodynamic effects on the process of autophagy.
In the scope of the Master's thesis, we reviewed the available databases and literature to determine which active substances can modulate the process of autophagy through their secondary pharmacological effects at their therapeutic concentrations and what is their mechanism of action. Thus, we gained insight into which active substance might be used in the future to treat autophagy-related diseases by simply altering the indication. In the Master's thesis, we have discovered that many drugs, which are already on the market, show an impact on the process of autophagy. However, only a few affect the autophagy at therapeutic concentrations. The effect on autophagy at therapeutic concentrations has been shown by maraviroc and protease inhibitors (antiviral drugs), macrolides (antibacterial drugs), bortezomib (an anticancer drug), mibefradil and other T-type calcium channel blockers (cardiovascular drugs), antimalarial drugs (chloroquine and hydroxychloroquine) and carbamazepine, valproic acid, topiramate and levetiracetam (antiepileptics). The aforementioned drugs have the potential to be used for treatment of several types of cancer (by inhibiting the process of autophagy either suppressing tumor cell growth or causing tumor cell death), Alzheimer's disease (activated autophagy prevents amyloid plaque formation) and coronary heart disease (activated autophagy prevents lipids formation). Since all of the listed active substances have already been approved for the primary indication and all preclinical studies have been performed, new alternatives for the treatment of these diseases could be found in a conveient and inexpensive manner by repurposing the active substance. However, it should be noted that many more studies should be conducted and the mechanism of action on the process of autophagy should be investigated in detail to gain a better understanding of secondary pharmacodynamics on the process of autophagy.
|
