Investigating the effects of new lysyl oxidase (LOX) and lysyl oxidase like 2 (LOXL2) inhibitors on clear cell renal cell carcinoma invitro

Alkhfaji, Abir (2018) Investigating the effects of new lysyl oxidase (LOX) and lysyl oxidase like 2 (LOXL2) inhibitors on clear cell renal cell carcinoma invitro. Masters by Research thesis (MSc), Manchester Metropolitan University.

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Abstract

Renal cell carcinoma (RCC) is a common type of cancer worldwide. It is found mainly in adults, and its incidence in males is higher than in females. RCC has different histological subtypes, the commonest (>80%) being clear cell RCC (ccRCC), which originates in the proximal convoluted tubes. ccRCC is highly resistant to chemotherapy. Even targeted therapies do not lead to complete responses in the majority of the patients. New treatment options to ccRCC patients need to be developed. The lysyl oxidase family consists of lysyl oxidase (LOX) and LOX like enzymes (LOXL). LOX and LOXL2 have varying degrees of similarity in their structures and functions. They catalyse the crosslinking of the extra cellular matrix (ECM) proteins and promotes tumour progression and metastasis. The critical roles of LOX and LOXL2 in cancer (including ccRCC) development potentiate them as therapeutic targets. In this project, anti-cancerous properties of novel compound-1, 4 and 5 were investigated which include studying their effects on the proliferation, viability, adhesion, migration, and apoptosis of Caki-2 cells in vitro, as well as their regulation on the expression of LOX and LOXL2 and cellular signalling pathways. The results show that compound-1, 4 and 5 significantly reduced the expression of LOX/ LOXL2 and LOX activity in Caki-2 cells. All the three compounds displayed various degrees of anti-proliferation, anti-migration, inhibition of cell-ECM adhesion, and induction of apoptosis effects. The anti-ccRCC effects of compound-4, such as hindering cell cycle progression and inducing cell apoptosis, were stronger than compound-1 and 5 in vitro. The studies on cellular signalling pathways revealed that RRM2, CDKN1B, CXCL16 and CD98HC were significantly downregulated in all three compounds treated cells in comparison to the negative control. The expressions of MMP9 and CXCL12 were downregulated in compound-4 and 5 treated cells, but upregulated in compound-1 treated cells. In conclusion, this study showed the three novel compounds are potential inhibitors of LOX/LOXL2. They displayed variable anti-cancer activities in vitro. They may provide potential therapeutic strategies for the treatment of cancer by inhibiting LOX/LOXL2. Compound-4 might hold greater therapeutic promise for ccRCC treatment in the future.