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

Sotiris Kyriakou, William Cheung, Theodora Mantso, Melina Mitsiogianni, Ioannis Anestopoulos, Stephany Veuger, Dimitris T. Trafalis, Rodrigo Franco, Aglaia Pappa, David Tetard, Mihalis I Panayiotidis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
199 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)971-986
Number of pages16
JournalInvestigational New Drugs
Volume39
Issue number4
Early online date23 Feb 2021
DOIs
Publication statusPublished - 1 Aug 2021

Keywords

  • Apoptosis
  • Ceramide
  • Glutathione
  • Melanoma
  • Metal chelators
  • Oxidative stress

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