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Hydroxychloroquine

Plaquenil

Autophagy inhibitor (lysosomal alkalinizer)

Evidence Score

42

preclinical
Mechanism of Action

Accumulates in lysosomes, raising intralysosomal pH and blocking autophagic flux at the final degradation step. SDH-deficient tumors are under chronic metabolic stress from TCA cycle disruption and ROS, and rely on BECN1-mediated autophagy to recycle damaged mitochondria and replenish metabolic substrates. Blocking lysosomal degradation removes this survival mechanism. Clinical rationale is supported by multiple trials combining HCQ with mTOR inhibitors (everolimus) or temozolomide in neuroendocrine tumors and sarcomas — HCQ prevents the autophagy that would otherwise rescue cells from these metabolic insults (Levy et al., Cancer Discov 2014, PMID: 25249453; NCT03283150; NCT01023737). Favorable safety profile from decades of use in lupus/rheumatoid arthritis.

Pathway Connections
Autophagy / Survival

Metabolic stress from SDH loss triggers autophagy as a survival mechanism. Cells rely on autophagy to maintain metabolic homeostasis under energy stress.

Upstream event:

Metabolic stress + nutrient sensing dysregulation

Downstream effects:

Autophagosome formationLysosomal degradationMetabolic homeostasis maintenanceSurvival under stress
Molecular Targets

BECN1

Beclin-1

downstream

Core autophagy initiation protein; part of the PIK3C3/VPS34 complex that nucleates autophagosomes. In SDH-deficient tumors, chronic metabolic stress from TCA disruption upregulates autophagy via BECN1. Lysosomal inhibitors (chloroquine, hydroxychloroquine) block the terminal step of autophagic flux, depriving tumor cells of this survival mechanism.

UniProt: Q14457

Quick Facts
FDA Approved

Approved Indications

  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Malaria prophylaxis and treatment
ChEMBL IDCHEMBL1377
PubChem CID3652
Evidence

Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.

Coming in Phase 3

For research exploration only — not medical advice. Consult your doctor before acting on any information.

AI Analysis

Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.