A novel methylated analogue of L-Mimosine exerts its therapeutic potency through ROS production and ceramide-induced apoptosis in malignant melanoma

Kyriakou, Sotiris, Cheung, William, Mantso, Theodora, Mitsiogianni, Melina, Anestopoulos, Ioannis, Veuger, Stephany, Trafalis, Dimitris T., Franco, Rodrigo, Pappa, Aglaia, Tetard, David and Panayiotidis, Mihalis (2021) A novel methylated analogue of L-Mimosine exerts its therapeutic potency through ROS production and ceramide-induced apoptosis in malignant melanoma. Investigational New Drugs. ISSN 0167-6997 (In Press)

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Official URL: https://doi.org/10.1007/s10637-021-01087-5

Abstract

Melanoma is an aggressive and highly metastatic type of skin cancer where the design of new therapies is of utmost importance for the clinical management of the disease. Thus, we have aimed to investigate the mode of action by which a novel methylated analogue of L-Mimosine (e.g., L-SK-4) exerts its therapeutic potency in an in vitro model of malignant melanoma. Cytotoxicity was assessed by the Alamar Blue assay, oxidative stress by commercially available kits, ROS generation, caspase 3/7 activation and mitochondrial membrane depolarisation by flow cytometry, expression of apoptosis-related proteins by western immunoblotting and profiling of lipid biosynthesis by a metabolomic approach. Overall, higher levels of ROS, sphingolipids and apoptosis were induced by L-SK-4 suggesting that the compound’s therapeutic potency is mediated through elevated ROS levels which promote the upregulation of sphingolipid (ceramide) biosynthesis thus leading to the activation of both extrinsic and intrinsic apoptosis, in an experimental model of malignant melanoma.

Item Type: Article
Additional Information: Funding information: This work was supported by start-up funds to MIP including a PhD studentship obtained from DT in support of SK provided by the Multi-Disciplinary Research Theme in “Bio-economy” of Northumbria University.
Uncontrolled Keywords: Metal chelators, Melanoma, Oxidative stress, Glutathione, Ceramide, Apoptosis
Subjects: B200 Pharmacology, Toxicology and Pharmacy
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Elena Carlaw
Date Deposited: 16 Feb 2021 13:07
Last Modified: 24 Feb 2021 16:02
URI: http://nrl.northumbria.ac.uk/id/eprint/45443

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