TY - JOUR
T1 - A novel methylated analogue of L-Mimosine exerts its therapeutic potency through ROS production and ceramide-induced apoptosis in malignant melanoma
AU - Kyriakou, Sotiris
AU - Cheung, William
AU - Mantso, Theodora
AU - Mitsiogianni, Melina
AU - Anestopoulos, Ioannis
AU - Veuger, Stephany
AU - Trafalis, Dimitris T.
AU - Franco, Rodrigo
AU - Pappa, Aglaia
AU - Tetard, David
AU - Panayiotidis, Mihalis I
N1 - 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.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Ceramide
KW - Glutathione
KW - Melanoma
KW - Metal chelators
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85101333921&partnerID=8YFLogxK
U2 - 10.1007/s10637-021-01087-5
DO - 10.1007/s10637-021-01087-5
M3 - Article
C2 - 33624234
SN - 0167-6997
VL - 39
SP - 971
EP - 986
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 4
ER -