Aberrant fatty acid metabolism as an important prognostic marker in breast cancer

[J. V. Jovankić]

189 listova

Prenamena lekova je proces ispitivanja i razvoja već odobrenih lekova zarad identifikacije novih terapijskih indikacija. Ovaj proces poslednjih godina ima značajno mesto u razvoju novih antitumorskih agenasa u borbi protiv karcinoma dojke. U okviru ove doktorske disertacije ispitivan je antitumorski efekat Orlistata i Simvastatina, lekova koji se koriste za lečenje hiperholesterolemije i gojaznosti kao i biljke Ocimum minimum L. koja se u narodnoj medicini koristi za lečenje istih stanja. Testirani tretmani značajno smanjuju vijabilnost i indukuju proapoptopski efekat kod MDA-MB-231 i MDA-MB-468 ćelija karcinoma dojke, dok u zdravim MRC-5 pokazuju znatno slabiji efekat. Testirani tretmani su narušili redoks homeostazu karcinomskih ćelija što je dovelo do modulacije ekspresije gena i proteina koji su uključeni u proces biosinteze masnih kiselina i angiogeneze. Na osnovu rezultata može se zaključiti da ovi tretmani imaju značajan potencijal kao antitumorski agensi. Druga faza istraživanja zasniva se na praćenju genske i proteinske ekspresije ključnih parametra biosinteze masnih kiselina (ACLY, FASN) na uzorcima tkiva pacijenata sa karcinomom dojke. Ekspresija ACLY i FASN na transkripcionom odnosno proteinskom nivou je povišena u uzorcima karcinoma i mikrookruženja u zavisnosti od kliničkopatološke klasifikacije što ukazuje na agresivan fenotip karcinoma dojke. Ispitivani parametri se mogu koristiti kao potencijalni tumor markeri i zahtevaju dodatna ispitivanja. Primenom različitih algoritama mašinskog učenja, u trećoj fazi istraživanja, pokazano je da FASN značajno doprinosi poboljšanju TNM klasifikacionog modela karcinoma dojke. Ovaj rezultat je od posebnog značaja za preciznije postavljanje dijagnoze i određivanje terapijskog protokola.

Drug repurposing is process of testing and developing already approved drugs to identify new therapeutic indications. In recent years, this process has played a significant role in the development of new antitumor agents for breast cancer therapy. In this doctoral dissertation, the antitumor effect of Orlistat and Simvastatin, drugs used to treat hypercholesteremia and obesity was investigated, as well as herb Ocimum minimum L., which is used in tradicional medicine for same conditions. These treatments significantly reduce the viability and induce proapoptotic effect in MDA-MB-231 and MDA-MB-468 breast cancer cells, while in normal MRC-5 show non-significant effect. These treatments disrupted redox homeostasis of cancer cells, which led modulation in expression of genes and proteins involved in fatty acid biosynthesis and angiogenesis. It can be concluded that these treatments have significant potential as antitumor agents and deserve further investigation. The second part of research is based on monitoring of gene and protein expression of key parameters of fatty acid biosynthesis on tissue samples from patients with breast cancer. The expression of ACLY and FASN at transcriptional and protein levels is elevated in cancer and/or microenvironment samples, depending on clinical-pathological classification, which indicates an aggressive phenotype of this cancer. The investigated parameters can be used as potential tumor markers and require further in vitro and in vivo testing. By applying different machine learning algorithms, it was shown that FASN significantly contributes to improvement TNM clasification model of breast cancer. This result is of particular importance for making a more precise diagnosis at these patients.

ngiogeneza, biosinteza masnih kiselina, karcinom dojke, mašinsko učenje, Orlistat, Ocimum minimum, prenamena lekova, Simvastatin.

angiogenesis, fatty acid biosynthesis, breast cancer, machine learning, Orlistat, Ocimum minimum, drug repurposing, Simvastatin.

577.2:591.1(043.3) 618.19-006-085(043.3)

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