Database Query Results : Amodiaquine, ,

AMQ, Amodiaquine: Click to Expand ⟱
Features:

Amodiaquine — a synthetic 4-aminoquinoline antimalarial (AMQ; AQ) closely related to chloroquine, most often used clinically as part of artemisinin-based combination therapy (e.g., artesunate–amodiaquine). It is rapidly biotransformed (notably via CYP2C8) to the active metabolite desethylamodiaquine (DEAQ), which drives much of the in-vivo exposure and pharmacology. Beyond antimalarial activity, amodiaquine behaves as a lysosomotropic weak base in mammalian cells and has been investigated preclinically as an autophagy/lysosome pathway modulator and as a cancer-sensitizing agent.

Primary mechanisms (ranked):

  1. Lysosomotropism with lysosomal alkalinization and functional blockade of autophagy–lysosome flux (context-dependent).
  2. Ribosome biogenesis suppression via inhibition of RNA polymerase I–dependent rRNA transcription with downstream ribosomal-stress signaling and p53 stabilization (model-dependent).
  3. Proteostasis stress signaling downstream of lysosome/autophagy dysfunction (UPR/ISR activation; model-dependent).
  4. Redox and mitochondrial stress as a secondary consequence of impaired clearance and stress signaling (dose-dependent).
  5. Chemo-/stress-sensitization phenotypes (e.g., starvation- or chemotherapy-enhanced killing) linked to autophagy–lysosome blockade (model-dependent).

Bioavailability / PK relevance: Orally bioavailable; parent AQ is short-lived (hours) while DEAQ persists for days to weeks and dominates systemic exposure. This long metabolite tail is clinically relevant for malaria efficacy and for any repurposing scenario where sustained exposure amplifies both on-target and off-target risks.

In-vitro vs systemic exposure relevance: Many anticancer/autophagy studies use micromolar concentrations that may exceed safely achievable free systemic levels; interpretation should account for lysosomotropic intracellular trapping and tissue distribution, and for toxicity constraints that limit dose-escalation.

Clinical evidence status: Established antimalarial use (including WHO-recommended ACT combinations). Anticancer use remains preclinical/early translational (cell and animal models); no established oncology RCT evidence as a standalone anticancer therapeutic.

Amodiaquine is a synthetic 4-aminoquinoline compound initially developed as an antimalarial agent. Like chloroquine, it is based on the quinoline scaffold and was chemically synthesized rather than being directly extracted from natural products.

Pathways:
-Autophagy Inhibition:
Inhibition of autophagy and lysosomal dysfunction can lead to cellular stress through accumulation of damaged proteins and organelles, triggering pathways such as the unfolded protein response (UPR) and increasing reactive oxygen species (ROS).

Mechanistic axes reported for amodiaquine in cancer-relevant models

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Autophagy–lysosome function Autophagic flux ↓; lysosomal function ↓; stress sensitivity ↑ (model-dependent) Autophagic flux ↓ (context-dependent) P/R Functional autophagy inhibition Lysosomotropic weak-base behavior can phenocopy “chloroquine-like” autophagy inhibition; effects depend on exposure, cell type, and baseline autophagy reliance.
2 Ribosome biogenesis and nucleolar stress Pol I activity ↓; rRNA transcription ↓; p53 signaling ↑ (model-dependent) Potential p53 stress signaling ↑ (context-dependent) R/G Growth arrest / stress signaling Reported as Pol I catalytic subunit destabilization with ribosomal-stress mediators driving p53 stabilization; oncology relevance is tumor genotype (p53 status) dependent.
3 UPR / ISR proteostasis signaling UPR/ISR ↑ (model-dependent) UPR/ISR ↑ (context-dependent) R/G Proteostasis stress response Lysosome/autophagy blockade can accumulate damaged proteins/organelles, provoking ER stress programs; directionality varies by model and dose.
4 Mitochondria and apoptotic stress Mitochondrial stress ↑; apoptosis ↔/↑ (dose- and model-dependent) Mitochondrial stress ↑ (high concentration only) R/G Stress-amplified cell death Observed killing is often conditional on co-stress (starvation/chemo) or high exposure; not a uniformly direct apoptogen across models.
5 ROS modulation ROS ↑ (dose-dependent; secondary) ROS ↔/↑ (context-dependent) P/R Secondary oxidative stress Frequently downstream of lysosomal dysfunction/mitochondrial stress; not necessarily a primary initiating mechanism.
6 Chemosensitization / stress-sensitization ChemoSen ↑ (model-dependent) Potential toxicity synergy ↑ (context-dependent) R/G Augmented response to therapy/stress Preclinical work reports sensitization to starvation- and chemotherapy-induced death consistent with autophagy/lysosome blockade as the enabling mechanism.
7 Drug transport and resistance phenotypes Efflux/accumulation ↔ (model-dependent) Efflux/accumulation ↔ R Intracellular distribution effects Nestronics flags mixed “eff↑/eff↓”; mechanistically this may reflect altered lysosomal sequestration and compound partitioning rather than direct transporter inhibition.
8 Clinical Translation Constraint Therapeutic window limited by systemic toxicity risk Hepatic and hematologic risk signals are key constraints G Dose-limiting safety and exposure ceiling Amodiaquine is associated with rare but serious adverse reactions (notably hepatotoxicity and agranulocytosis, especially with prolonged/prophylactic use), and DEAQ’s long persistence complicates safety management in repurposing scenarios.

TSF legend: P: 0–30 min   R: 30 min–3 hr   G: >3 hr
Scientific Papers found: Click to Expand⟱
1440- AMQ,    Lysosomotropism depends on glucose: a chloroquine resistance mechanism
- in-vitro, BC, 4T1
eff↑, Apoptosis↓, Necroptosis↑, eff↓, ChemoSen↑, eff↓,

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Cell Death ⓘ

Apoptosis↓, 1,   Necroptosis↑, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   eff↓, 2,   eff↑, 1,  
Total Targets: 5

Pathway results for Effect on Normal Cells:


Total Targets: 0

Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:272  Target#:%  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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