1182 Melatonin enhances BRAF/MEK inhibitors-induced disturbances in mitochondrial homeostasis and oncogenic pathways in human melanoma

Melanoma is a leading cause of cancer deaths worldwide. Although targeted therapy and immunotherapy have improved the outcome patients with metastatic disease, unwanted side effects are problem. Herein, by using human melanoma cell lines in vitro, we explore that melatonin enhances anti-tumor activity commonly used BRAF/MEK inhibitors, i.e. vemurafenib (VF) cobimetinib (CB), respectively. Our results demonstrated compared VF/CB alone, significantly reduced proliferation read-outs (Colony, Drop Scratch assay) induced apoptosis (cl. Casp-9, -3, PARP) cells. Concurrently, VF/CB+melatonin decreased invasiveness-related protein (E-cadherin), inducible nitric oxide synthase (iNOS), epithelial adhesion molecule (EpCAM), proliferating nuclear antigen (PCNA); important players tumorgenesis, tumor growth, invasion metastasis. In addition, also found combined treatment caused significant mechanistic changes cellular bioenergetics (i) uncoupling oxidative phosphorylation (OXPHOS), (ii) attenuation glycolysis (Seahorse assessment), (iii) dissipation mitochondrial transmembrane potential (mtΔΨ) (FACS), (iv) morphology (TEM). extend previously published data they provide new perspectives evidence for introduction as an add-on complementary future melanoma-affected patients.