Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma

Abstract

The anticancer activity of a series of novel synthesized, hydroxypyridone-based metal chelators (analogues of L-mimosine) was evaluated in an in vitro model of melanoma consisting of malignant melanoma (A375), non-melanoma epidermoid carcinoma (A431) and immortalized non-malignant keratinocyte (HaCaT) cells. More specifically, we have demonstrated that the L-enantiomer of a methylated analogue of L-mimosine (compound 22) can exert a potent anticancer effect in A375 cells when compared to either A431 or HaCaT cells. Moreover, we have demonstrated that this analogue has the ability to i) promote increased generation of reactive oxygen species (ROS), ii) activate both intrinsic and extrinsic apoptosis and iii) induce perturbations in cell cycle growth arrest. Our data highlights the potential of compound 22 to act as a promising therapeutic agent against an in vitro model of human malignant melanoma.

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

“…The anti-cancer activity of hydroxypyridone-based (HOPO) metal chelators has been documented, in the past, by others [16,17] as well as by our research group [18]. More speci cally, we have previously shown that treatment of malignant melanoma (A375) cells with a novel N-substituted 3,4-HOPO compound (L-SK-4) can induce the activation of both intrinsic and extrinsic apoptotic cascades as well as perturbations in cell cycle and ROS homeostasis [18]. Interestingly, an immortalized, non-tumorigenic keratinocyte cell line was shown to be more resistant to the action of L-SK-4; thus, proving the compound's speci city against its potential target.…”

“…SK-1, SK-2, SK-3, D-SK-4, L-SK-4 and SK-5 were previously synthesized, puri ed and characterized [18]. GSH, resazurin sodium salt and Myriocin were purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

“…A375 cells were plated in 100 mm dishes and cultured overnight at 37 o C. Next day, cells were treated with L-SK-4 (100 µM) with or without pre-treatment with either GSH (1.5 mM) or myriocin (50 nM) for 24, 48 and 72 hr. Cell lysates were prepared and obtained as previously described [18]. Protein content was determined by utilizing the BCA protein assay kit (Thermo Scienti c, Waltham, MA, USA), according to the manufacturer's protocols.…”

“…Consequently, we have employed an in vitro model of malignant melanoma consisting of non-metastatic (A375 and B16F-10) as well as metastatic (VMM1 and Hs294T) melanoma cell lines in addition to non-melanoma epidermoid carcinoma (A431) and nonmalignant immortalized melanocyte neighbouring keratinocyte (HaCaT) cells. The aim of this study was to investigate the mode of action by which L-SK-4 activates the apoptotic response in order to delineate the underlying mechanisms by which it exerts its previously described therapeutic potency [18].…”

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

“…In a previous study published by our group, we have documented the anti-cancer ability of a newly synthesized series of hydroxypyridinone-based analogues of L-Mimosine in an in vitro model of malignant melanoma. From these compounds, a methylated N-substituted hydroxypyridinone form was shown to be the most cytotoxic by exerting a higher potency against A375 than A431 and HaCaT cells [18]. Herein, we performed a kinetic determination of ROS induction in a series of HOPO-based analogues of L-Mimosine in an attempt to characterize the mode of action of this class of , ### , ◊◊◊ at p < 0.001 compounds.…”