Examination of selected drug classes modulatory actions on the process of autophagy

Avtofagija je kataboličen proces razgradnje celici lastnih sestavin s pomočjo lizosomov, ki poteka v vseh vrstah celic. Pri tem celica odstrani nefunkcionalne organele, jih reciklira in tako pridobi nujno potrebna hranila. Gre za natančno reguliran proces, ki vzdržuje celično ravnovesje. Po drugi strani pa je proces avtofagije lahko močno povezan z raznimi človeškimi obolenji, kot so rakava obolenja, bolezni živčevja, kardiovaskularne bolezni, itd. Tudi nekateri patogeni mikrobi lahko vplivajo na potek avtofagije in jo obrnejo sebi v prid. Avtofagija je torej lahko v določenih primerih zaželena, v drugih pa ne. Z različnimi majhnimi molekulami, tudi nekaterimi zdravilnimi učinkovinami, lahko moduliramo proces avtofagije, kar se lahko potem izkorišča v terapevtske namene. Številne zdravilne učinkovine, katerih primarna indikacija ni delovanje na proces avtofagije, izkazujejo sekundarne farmakodinamske učinke prav na proces avtofagije. V magistrski nalogi smo s pregledovanjem baz podatkov in ustrezne literature ugotavljali, katere zdravilne učinkovine lahko preko sekundarnih farmakoloških učinkov modulirajo proces avtofagije že pri njihovih terapevtskih koncentracijah in kakšen je njihov mehanizem delovanja. Tako smo dobili vpogled, katere zdravilne učinkovine bi v prihodnosti lahko morda izkoriščali za zdravljenje z avtofagijo povezanih bolezni s preprosto spremembo indikacije. Ugotovili smo, da lahko številne zdravilne učinkovine, ki so že na tržišču, modulirajo proces avtofagije, nekatere pa izkazujejo vpliv na avtofagijo že pri terapevtskih koncentracijah. Vpliv na proces avtofagije pri terapevtskih koncentracijah izkazujejo maravirok in zaviralci proteaz, ki spadajo med predstavnike protivirusnih zdravilnih učinkovin, makrolidi (protibakterijske ZU), bortezomib (protirakava ZU), mibefradil in ostali zaviralci kalcijevih kanalčkov tipa T (kardiovaskularne ZU), klorokin in hidroksiklorokin (antimalariki) ter karbamazepin, valprojska kislina, topiramat in levetiracetam (antiepileptiki). Omenjene zdravilne učinkovine imajo zato potencial za več različnih indikacij, še posebej za zdravljenje več vrst raka (z zaviranjem procesa avtofagije bodisi zatrejo rast tumorskih celic ali pa povzročijo smrt tumorskih celic), Alzheimerjeve bolezni (pospešena avtofagija prepreči nastajanje amiloidnih plakov) in koronarnih srčnih bolezni (z aktivacijo avtofagije pride do zmanjševanja lipidov). Ker so vse izmed naštetih učinkovin že odobrene za primarno indikacijo in imajo opravljene vse predklinične študije, bi s prenamembo zdravilne učinkovine lahko na preprost in poceni način prišli do novih alternativ za zdravljenje omenjenih bolezni. Pri tem pa se je potrebno zavedati, da bi bilo potrebno narediti še veliko študij in podrobno raziskati mehanizem delovanja na proces avtofagije in s tem pridobiti boljše razumevanje sekundarne farmakodinamike na proces avtofagije.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\u27s 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\u27s 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\u27s 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