Lapachol / ROS Cancer Research Results

LapC, Lapachol: Click to Expand ⟱
Features:
Lapachol is a natural naphthoquinone originally derived from the heartwood of the lapacho tree (Tabebuia species).
-lapachol is an analog of shikonin

Pathways:

Oxidative Stress and ROS Generation
–Like many quinones, lapachol can undergo redox cycling that generates reactive oxygen species (ROS).
-Oxidative damage to DNA, proteins, and lipids, thereby promoting cancer cell death.
-cell cycle at specific checkpoints (commonly at G0/G1 or G2/M phases)
-Inhibition of the NF‑κB signaling pathway
–MAPK Pathways

-ic50 cancer cells 10-50uM, normal cells higher (existence of a therapeutic window)

Lapachol — a naturally occurring prenylated 1,4-naphthoquinone, chemically 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone, found principally in the heartwood of Tabebuia/Handroanthus species such as pau d’arco/lapacho. It is a natural-product small molecule and experimental pharmacologic agent rather than an approved anticancer drug. Lapachol has several experimentally supported molecular targets, notably RSK2, PKM2 and DHODH, with additional evidence for topoisomerase inhibition and quinone-associated redox effects.

Primary mechanisms (ranked):

  1. RSK2 inhibition with suppression of downstream proliferative signaling and induction of mitochondrial intrinsic apoptosis.
  2. PKM2 inhibition with suppression of aerobic glycolysis, reduced ATP generation and increased metabolic vulnerability.
  3. DHODH inhibition with suppression of de novo pyrimidine synthesis and proliferation.
  4. Mitochondrial intrinsic apoptosis involving BAX, cytochrome c and caspase-3/7 activation.
  5. Topoisomerase I and II inhibition with impaired DNA topology, DNA damage and antiproliferative effects in selected models.
  6. Quinone redox cycling and ROS generation (secondary/context-dependent), potentially enhanced in cells capable of efficient quinone reduction.
  7. Cell-cycle arrest and suppression of clonogenic growth and migration, varying substantially by tumor model.

Bioavailability / PK relevance: Lapachol is orally absorbable in animal models, with reported oral bioavailability approximately 55–77% for lapachol in one preclinical PK study; this should not be assumed to represent human exposure. It binds strongly to human serum albumin and is relatively hydrophobic, affecting distribution and free-drug exposure. Historical human studies found that plasma concentrations believed necessary for anticancer activity required very large oral doses, creating a major dose-limiting translational problem.

In-vitro vs systemic exposure relevance: Most modern anticancer studies use micromolar lapachol concentrations, frequently in the approximately 10–100 μM range depending on model and endpoint. Historical clinical work indicates that maintaining sufficiently high systemic concentrations is difficult without substantial toxicity; therefore many in-vitro anticancer exposures may exceed realistically sustainable human free-drug exposure. Derivatives and metal complexes of lapachol can be considerably more potent but should not be interpreted as evidence for parent lapachol itself.

Clinical evidence status: Preclinical with limited historical human exposure. A small early cancer clinical study was performed in the 1970s, but development was discontinued because high drug concentrations were required and dose-limiting toxicity, particularly anticoagulant effects and prolonged prothrombin time, emerged. No validated modern RCT evidence supports lapachol as an anticancer treatment, and it is not an approved cancer therapy.

Lapachol Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 RSK2 signaling ↓ ↔ / ↓ (context-dependent) R/G Suppression of proliferative signaling Direct RSK2 inhibition demonstrated in ESCC models; growth inhibition was strongly dependent on RSK2 expression and was associated with intrinsic apoptosis.
2 PKM2 and glycolysis ↓ ↔ / ↓ (context-dependent) R/G Reduced glycolytic ATP production Lapachol inhibits purified PKM2 and tumor-cell PKM2 activity, decreases glycolytic flux and ATP, and increases reliance on mitochondrial oxidative metabolism.
3 DHODH and pyrimidine synthesis ↓ ↓ proliferating cells R/G Reduced de novo pyrimidine synthesis Direct DHODH binding and inhibition are supported by biochemical studies and a human DHODH–lapachol crystal structure. The mechanism is not cancer-specific and may also suppress proliferating lymphocytes.
4 Mitochondrial intrinsic apoptosis ↑ ↔ / ↑ (dose-dependent) R/G Caspase-dependent apoptosis Associated with ↑ BAX, ↑ cytochrome c release, ↑ caspase-3/7 activity and PARP cleavage in responsive cancer models.
5 Topoisomerase I and II ↓ ↓ (high concentration) R/G DNA damage and impaired DNA topology Inhibition of TOP1 and TOP2 has been demonstrated in glioma models. Evidence is less extensive than for RSK2, PKM2 and DHODH.
6 ATP and metabolic fitness ↓ ↔ / ↓ (dose-dependent) R/G Energetic stress Primarily downstream of PKM2 inhibition and metabolic rewiring rather than a discrete molecular target.
7 Mitochondrial respiration ↑ (context-dependent) ↔ R Compensatory oxidative metabolism PKM2 inhibition can shift melanoma cells away from glycolysis toward increased oxygen consumption, creating vulnerability to mitochondrial perturbation.
8 ROS and quinone redox cycling ↑ (context-dependent) ↑ (dose-dependent) P/R Oxidative stress and macromolecular damage Mechanistically plausible for reducible naphthoquinones and supported by naphthoquinone redox biology, but ROS should be treated as a secondary mechanism for parent lapachol rather than its best-established primary anticancer target.
9 DNA damage ↑ ↑ (high concentration) R/G Genotoxic stress Can arise downstream of topoisomerase inhibition and oxidative stress.
10 Cell-cycle progression ↓ ↓ (dose-dependent) G Cell-cycle arrest Sub-G1 accumulation and other checkpoint effects have been reported; the specific checkpoint varies by cell type and experimental system.
11 Clonogenic survival ↓ Not established G Reduced long-term proliferative capacity Demonstrated in ESCC and more recent bladder cancer models.
12 Migration ↓ Not established G Reduced tumor-cell motility Reported in bladder cancer and other experimental models; molecular basis remains less well established than the core metabolic targets.
13 Vitamin K recycling ↓ ↓ R/G Anticoagulant effect Lapachol inhibits vitamin K epoxide reductase and vitamin K quinone reductase. This provides a mechanistic explanation for prolonged prothrombin time observed at high exposure and represents an important safety limitation.
14 Clinical Translation Constraint ↓ therapeutic feasibility ↑ toxicity risk G Exposure-limited clinical utility Anticancer activity generally requires substantial micromolar exposure. Historical clinical studies encountered difficulty achieving effective plasma levels without anticoagulant toxicity; no modern clinical anticancer efficacy has been established.
P: 0–30 min    R: 30 min–3 hr    G: >3 hr

ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.
-mitochondria is the main source of reactive oxygen species (ROS) (and the ETC is heavily related)
ROS Homeostasis in Cancer Cells and Its Potential as a Therapeutic Target

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2 inhibition: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α inhibition: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1 inhibition:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK activation: regulates energy metabolism and can increase ROS levels when activated.
• mTOR inhibition: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90 inhibition: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Mevalonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day, -Dipyridamole typically 200mg 2x/day Combined effect research
-Lycopene typically 100mg/day range (note debatable as it mainly lowers NRF2)

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy 
ROS-Inducing Interventions in Cancer — Canonical + Mechanistic Reference
-generated from AI and Cancer database
ROS rating:  +++ strong | ++ moderate | + weak | ± mixed | 0 none
NRF2:        ↓ suppressed | ↑ activated | ± mixed | 0 none
Conditions:  [D] dose  [Fe] metal  [M] metabolic  [O₂] oxygen
             [L] light [F] formulation [T] tumor-type [C] combination




Item ROS↑ NRF2 Condition Mechanism Class Remarks 



ROS">Piperlongumine
+++ ↓ [D][T] ROS-dominant






ROS">Shikonin
+++↓/±[D][T]ROS-dominant






ROS">Vitamin K3 (menadione)
+++↓[D]ROS-dominant






ROS">Copper (ionic / nano)
+++↓[Fe][F]ROS-dominant






ROS">Sodium Selenite
+++↓[D]ROS-dominant






ROS">Juglone
+++↓[D]ROS-dominant






ROS">Auranofin
+++↓[D]ROS-dominant






ROS">Photodynamic Therapy (PDT)
+++0[L][O₂]ROS-dominant






ROS">Radiotherapy / Radiation
+++0[O₂]ROS-dominant






ROS">Doxorubicin
+++↓[D]ROS-dominant






ROS">Cisplatin
++↓[D][T]ROS-dominant






ROS">Salinomycin
++↓[D][T]ROS-dominant






ROS">Artemisinin / DHA
++↓[Fe][T]ROS-dominant






ROS">Sulfasalazine
++↓[C][T]ROS-dominant






ROS">FMD / fasting
++↓[M][C][O₂]ROS-dominant






ROS">Vitamin C (pharmacologic)
++↓[Fe][D]ROS-dominant






ROS">Silver nanoparticles
++±[F][D]ROS-dominant






ROS">Gambogic acid
++↓[D][T]ROS-dominant






ROS">Parthenolide
++↓[D][T]ROS-dominant






ROS">Plumbagin
++↓[D]ROS-dominant






ROS">Allicin
++↓[D]ROS-dominant






ROS">Ashwagandha (Withaferin A)
++↓[D][T]ROS-dominant






ROS">Berberine
++↓[D][M]ROS-dominant






ROS">PEITC
++↓[D][C]ROS-dominant






ROS">Methionine restriction
+↓[M][C][T]ROS-secondary






ROS">DCA
+±[M][T]ROS-secondary






ROS">Capsaicin
+±[D][T]ROS-secondary






ROS">Galloflavin
+0[D]ROS-secondary






ROS">Piperine
+±[D][F]ROS-secondary






ROS">Propyl gallate
+↓[D]ROS-secondary






ROS">Scoulerine
+?[D][T]ROS-secondary






ROS">Thymoquinone
±±[D][T]Dual redox






ROS">Emodin
±±[D][T]Dual redox






ROS">Alpha-lipoic acid (ALA)
±↑[D][M]NRF2-dominant






ROS">Curcumin
±↑/↓[D][F]NRF2-dominant






ROS">EGCG
±↑/↓[D][O₂]NRF2-dominant






ROS">Quercetin
±↑/↓[D][Fe]NRF2-dominant






ROS">Resveratrol
±↑[D][M]NRF2-dominant






ROS">Sulforaphane
±↑↑[D]NRF2-dominant






ROS">Lycopene
0↑—Antioxidant






ROS">Rosmarinic acid
0↑—Antioxidant






ROS">Citrate
00—Neutral


Scientific Papers found: Click to Expand⟱
8167- LapC,    Characterization of lapachol cytotoxicity: contribution of glutathione depletion for oxidative stress in Saccharomyces cerevisiae
- in-vitro, Nor, NA
*GSH↓, *SOD1↓, *lipid-P↑, *ROS↑,

Showing Research Papers: 1 to 1 of 1

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

Pathway results for Effect on Cancer / Diseased Cells:


Total Targets: 0

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

GSH↓, 1,   lipid-P↑, 1,   ROS↑, 1,   SOD1↓, 1,  
Total Targets: 4

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
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#:300  Target#:275  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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