Repurposing Anticancer Drugs in Parkinson's Treatment: Molecular Pathways Driving Neuroprotection and Therapeutic Advancement.

Parkinson's disease (PD) affects 11.77 million people worldwide, projected to reach 17.27 million by 2035. Current dopamine replacement therapies provide symptomatic relief but lack disease-modifying effects. Drug repurposing offers advantages: reduced development time (3-12 vs 10-17 years) and costs ($40-80 million vs $1-3 billion). To examine the pathophysiological connections between cancer and PD and evaluate the therapeutic potential of repurposing anticancer drugs through shared molecular mechanisms. Analysis of shared pathways, including mitochondrial dysfunction, ubiquitin-proteasome dysregulation, protein aggregation, neurotrophic factors, apoptotic genes, Dual Tyrosine Kinase Inhibition, microRNAs, and inflammation. Examination of repurposed anticancer agents in preclinical and clinical PD studies. Mitochondria-targeted metformin analogues showed 1000-fold increased potency in MitoPark models, although Mito-Q failed in human trials. Ixazomib enhances α-synuclein clearance via autophagy in preclinical models. Nilotinib showed poor CNS penetration (< 0.3% in CSF), resulting in worsening motor outcomes. Relatlimab, trehalose, and lapatinib demonstrated preclinical benefits through inhibition of α-synuclein spread, mTOR-independent autophagy, and multi-pathway neuroprotection, respectively. The AZA-PD Phase 2 trial (azathioprine) demonstrated a favourable safety and tolerability profile and offered valuable insights into peripheral immune modulation in early PD, though it did not meet its primary endpoint of slowing disease progression. Key barriers include poor CNS penetration, narrow therapeutic windows (70% neuronal loss at diagnosis), differential safety requirements, and timing-dependent efficacy necessitating early intervention. Mechanistic convergence provides a rationale for repurposing drugs; however, clinical success requires addressing the unique challenges of neurodegeneration. Future approaches should focus on precision medicine, innovative delivery systems, and multi-target interventions rather than direct therapeutic translation.