Targeting Melatonin to Mitochondria Mitigates Castration-Resistant Prostate Cancer by Inducing Pyroptosis

Area of Science:

• Oncology
• Mitochondrial Biology
• Metabolic Pathways

Background:

• Prostate cancer often progresses to castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy.
• Targeting tumor metabolism, especially mitochondrial pathways, is a key strategy for overcoming CRPC.
• Melatonin (Mel) modification to a triphenylphosphonium (TPP) cation (Mito-Mel) enhances mitochondrial targeting and potency.

Purpose of the Study:

• To investigate the efficacy of mitochondria-targeted melatonin (Mito-Mel) in treating castration-resistant prostate cancer (CRPC).
• To explore the mechanisms by which Mito-Mel suppresses CRPC survival and induces anti-tumor responses.

Main Methods:

• Mitochondria-targeted melatonin (Mito-Mel) was synthesized by conjugating melatonin (Mel) with triphenylphosphonium (TPP).
• In vitro and in vivo models of CRPC were used to evaluate the anti-cancer effects of Mito-Mel.
• Mechanisms investigated included reactive oxygen species (ROS) generation, mitochondrial membrane potential, mitochondrial respiration (TCA cycle, OXPHOS), glycolysis, pyroptosis, and immune response.

Main Results:

• Mito-Mel demonstrated over 1000-fold increased potency compared to unmodified melatonin.
• Mito-Mel selectively targeted mitochondria, increased ROS generation, and disrupted mitochondrial membrane potential.
• Mito-Mel inhibited mitochondrial respiration (TCA cycle, OXPHOS) and suppressed CRPC metabolic adaptations like glycolysis.
• The compound induced tumor cellular pyroptosis and facilitated an anti-tumor immune response in CRPC models.

Conclusions:

• Mitochondria-targeted melatonin (Mito-Mel) exhibits significant anti-cancer efficacy against CRPC.
• This strategy effectively suppresses CRPC survival metabolism and induces cell death via pyroptosis.
• Mito-Mel shows promise as a novel therapeutic agent for CRPC by modulating tumor metabolism and enhancing immune response.