Hallachrome, a marine anthraquinone, impairs cell proliferation by acting as a functional mitochondrial uncoupler in A375 melanoma cells.

BACKGROUND: Melanoma remains one of the most lethal cancers due to its high metastatic capacity and resistance to current therapies, emphasizing the need for novel antineoplastic agents, including bioactive molecules from marine organisms, as potential sources of anticancer compound. AIMS: This study aimed to investigate, for the first time, the anticancer potential of Hallachrome (HC), an anthraquinone derived from the marine polychaete Halla parthenopeia, in A375 melanoma cells. METHODS: A375 melanoma cells were treated with HC in vitro to evaluate its impact on cell proliferation, migration, and morphology. Proteomic analysis was carried out to identify differentially expressed proteins in order to elucidate the biological processes modulated by the treatment. Mitochondrial morphology and function were analyzed by confocal microscopy and oxygen consumption rate, respectively, while mitochondrial membrane potential, intracellular reactive oxygen species (ROS) levels and GSH/GSSG ratio were evaluated by fluorescence-based assays. RESULTS: HC treatment significantly reduced melanoma cell proliferation and migration in vitro, accompanied by morphological alteration and apoptosis death. Proteomic profiling revealed differential expression of several proteins involved, for example, in membrane and mitochondria organization. Moreover, HC treatment induced severe mitochondrial dysfunction, characterized by ATP depletion, mitochondrial membrane depolarization, fragmentation of the mitochondrial network, altered intracellular ROS level and GSH/GSSG ratio. DISCUSSION: These findings suggest that HC inhibits melanoma cell survival by disrupting mitochondrial homeostasis and inducing energetic stress. Given the pivotal role of mitochondria in cancer progression, the ability of HC to interfere with mitochondrial functions supports its potential as a promising anticancer agent.