EXPLOITING MOLECULAR NETWORKS BY REPURPOSED DRUGS AND NOVEL SMALL MOLECULES IN HEPATOCELLULAR CARCINOMA CELLS AND STEM CELLS FOR NEW THERAPEUTIC OPTIONS

Date

2023-4-24

Author

NALBAT, ESRA

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Hepatocellular carcinoma (HCC) is one of the most prominent types of primary liver cancer and the second most lethal cancer worldwide. Current targeted therapeutic options are limited for advanced-stage HCC; hence there is an indispensable need for improvement in single or combinatorial targeted drug treatments for patient survival. Targeting cellular molecular networks involved in drug-resistant HCC cells and cancer stem cells both in silico and in vivo is a promising approach for novel therapeutics. Here, we retrieved HCC-specific signaling networks and constructed a directed network. Drug-target data from DrugBank was integrated into the network. Then, we applied the in silico attack strategy, we identified Amrinone, Thalidomide, Chloroquine Phosphate, Sunitinib, Pranlukast, Pseudoephedrine HCI, Brigatinib, Lenvatinib, and Regorafenib and their combinations as active drug candidates for HCC by in silico modeling of HCC specific signaling networks. In vivo, Sunitinib:Pseudoephedrine HCI and Sunitinib:Chloroquine Phosphate drug combinations were synergistically cytotoxic on HCC cells, the latter being the most bioactive. Transcriptome and proteome analyses of HCC cells with the selected drug combination treatments alter Wnt/β-catenin, cell cycle, and PI3K/AKT, MAPK, and EMT pathways. In addition to known drugs, bioactivities of novel isoxazole-piperazine were tested on HCC and their stem cells (LCSC). Compounds 21 and 23 caused oxidative stress-dependent apoptosis and cell cycle arrest. 1 and 59 were cytotoxic to LCSCs and reduced the CD133+/EpCAM+ population ratio along with OCT4 and NANOG protein levels in HCC cells. Hence novel isoxazole-piperazine compounds could serve as lead drug molecules against HCC cells and cancer stem cells. In conclusion, this thesis presents significant bioactivities of in silico identified and in vitro validated repurposed drugs and of novel isoxazole-piperazine derivatives as drug candidates for HCC.

Subject Keywords

hepatocellular carcinoma, drug repurposing, synergism, network biology, drug discovery

URI

https://hdl.handle.net/11511/103250

Collections

Graduate School of Informatics, Thesis