Nimbolide / Casp3 Cancer Research Results

Nimb, Nimbolide: Click to Expand ⟱
Features:
Nimbolide is a compound found in the neem tree (Azadirachta indica) and has been studied for its potential anti-cancer properties. nimbolide is a neem-derived tetranortriterpenoid limonoid from Azadirachta indica.

Research has shown that nimbolide has anti-proliferative and pro-apoptotic effects on various types of cancer cells, including breast, lung, colon, and prostate cancer cells. It has also been shown to inhibit the growth of cancer cells by inducing cell cycle arrest and apoptosis (programmed cell death).

Some of the ways in which nimbolide may help to prevent or treat cancer include:
-Inhibiting the activity of certain enzymes that are involved in cancer cell growth and survival
-Inducing the production of reactive oxygen species (ROS) that can damage cancer cells
-Inhibiting the formation of new blood vessels that are needed to support the growth of cancer cells
-Enhancing the effectiveness of chemotherapy and radiation therapy

Nimbolide — Nimbolide is a neem-derived tetranortriterpenoid limonoid from Azadirachta indica with preclinical anticancer activity across multiple tumor models. It is best classified as a small-molecule plant limonoid / electrophilic triterpenoid natural product rather than as “neem oil” or whole neem extract. Standard abbreviation is NB or NL. aliases: “neem limonoids,” “neem extract,” and “Azadirachta indica limonoids”

Primary mechanisms (ranked):

  1. Covalent modulation of the ubiquitin-proteasome axis, especially RNF114-dependent substrate recognition and p21 stabilization.
  2. Mitochondrial oxidative stress induction through ROS elevation and SOD2 suppression in susceptible cancer cells.
  3. Apoptosis activation through caspase signaling, mitochondrial stress, and survival-pathway suppression.
  4. STAT3 and NF-κB pathway inhibition, reducing inflammatory survival signaling, proliferation, invasion, and anti-apoptotic transcription.
  5. EMT, migration, invasion, angiogenesis, and metastasis suppression in preclinical models.
  6. Autophagy modulation, including inhibition of cytoprotective autophagy in some tumor contexts.
  7. DNA damage response leverage, including RNF114-linked PARP1 trapping and reported synthetic-lethality relevance in BRCA-mutated models.

Bioavailability / PK relevance: Nimbolide is hydrophobic and poorly water-soluble, so systemic translation is constrained by formulation, solubility, exposure, metabolism, and tissue delivery. Nanoparticle and carrier-based formulations are being explored preclinically to improve delivery and anticancer exposure.

In-vitro vs systemic exposure relevance: Most anticancer findings use purified nimbolide in cell culture or animal models; direct equivalence to oral neem preparations is not established. Common in-vitro low-micromolar activity should not be assumed achievable with dietary or crude neem exposure. Whole neem oil or extract is chemically heterogeneous and may not deliver predictable nimbolide exposure.

Clinical evidence status: Preclinical. Evidence is strong enough for a database entry as a mechanistically interesting anticancer natural product, but not as a clinically validated anticancer therapy. No approved oncology indication or clear nimbolide-specific cancer trial status was identified; clinical use should be treated as unsupported outside research contexts.

Nimbolide Cancer Mechanism Table

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 RNF114 ubiquitin ligase axis RNF114 substrate recognition ↓; p21 stabilization ↑; proliferation ↓ Likely context-dependent; selectivity depends on dependency on RNF114-regulated substrates R/G Cell-cycle suppression and targeted-protein-degradation relevance High mechanistic importance because nimbolide has a defined electrophilic target interaction and can be used as a covalent recruiter scaffold.
2 Mitochondrial ROS and SOD2 ROS ↑; SOD2 ↓; mitochondrial stress ↑; apoptosis ↑ Potential oxidative-stress risk at sufficient exposure; selectivity is model-dependent R/G Oxidative apoptosis and metastasis suppression Core in pancreatic cancer models; may be especially relevant where tumor cells depend on antioxidant buffering.
3 Apoptosis and caspase activation Caspase 3 ↑; caspase 8 ↑; caspase 9 ↑; survival ↓ Lower effect reported in some normal-cell comparisons, but not universally established G Programmed cell death induction Central downstream phenotype across many cancer models.
4 STAT3 inflammatory survival signaling STAT3 phosphorylation ↓; anti-apoptotic transcription ↓; invasion ↓ Could suppress normal inflammatory or repair signaling if systemic exposure is high R/G Reduced proliferation, survival, and metastatic signaling Important in prostate and pancreatic cancer contexts; likely intersects with ROS and NF-κB effects.
5 NF-κB and Wnt beta catenin NF-κB activation ↓; IκB degradation ↓; Wnt beta catenin signaling ↓ Potential immune and epithelial-homeostasis effects are context-dependent R/G Anti-inflammatory, anti-survival, and anti-proliferative signaling Broadly reported in neem/nimbolide literature, but pathway dominance varies by tumor model.
6 Autophagy survival axis Cytoprotective autophagy ↓; apoptosis ↑ Autophagy effects may be protective or harmful depending on tissue stress state G Removal of tumor stress-adaptation capacity Secondary but therapeutically relevant where autophagy supports tumor survival.
7 EMT migration invasion metastasis EMT markers ↓; migration ↓; invasion ↓; metastatic traits ↓ Could affect normal wound-healing pathways at sufficient exposure G Anti-metastatic phenotype Strong preclinical relevance; not yet clinically validated.
8 Angiogenesis Pro-angiogenic signaling ↓ Physiologic angiogenesis may be affected in repair contexts G Reduced tumor vascular support Best treated as secondary/contextual unless a specific cancer model demonstrates angiogenesis as the dominant effect.
9 PARP1 trapping and BRCA synthetic lethality PARP1 trapping ↑; BRCA-mutated vulnerability ↑ DNA repair stress possible in proliferating normal cells R/G DNA-repair vulnerability exploitation Mechanistically interesting and industry-relevant, but narrower than the general ROS and ubiquitin-ligase mechanisms.
10 Clinical Translation Constraint In-vitro potency does not guarantee tumor exposure; formulation-dependent activity Safety margin uncertain for systemic use; crude neem products are not equivalent to purified nimbolide G Limits clinical interpretation Major constraints are poor solubility, uncertain human PK, lack of oncology trials, botanical heterogeneity, and neem toxicity concerns.

P: 0–30 min R: 30 min–3 hr G: >3 hr
Casp3, CPP32, Cysteinyl aspartate specific proteinase-3: Click to Expand ⟱
Source:
Type:
Also known as CP32.
Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death.
As a key protein of apoptosis, caspase-3 can also cleave GSDME and induce pyroptosis. Loss of caspase activity is an important cause of tumor progression.
Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been puzzling. Recent studies suggest subapoptotic caspase-3 activity may promote oncogenic transformation, a possible explanation for the enigmatic overexpression of PC-3. Herein, the overexpression of PC-3 in cancer and its mechanistic basis is reviewed; collectively, the data suggest the potential for exploitation of PC-3 overexpression with PC-3 activators as a targeted anticancer strategy.
Caspase 3 is the main effector caspase and has a key role in apoptosis. In many types of cancer, including breast, lung, and colon cancer, caspase-3 expression is reduced or absent.
On the other hand, some studies have shown that high levels of caspase-3 expression can be associated with a better prognosis in certain types of cancer, such as breast cancer. This suggests that caspase-3 may play a role in the elimination of cancer cells, and that therapies aimed at activating caspase-3 may be effective in treating certain types of cancer.
Procaspase-3 is a apoptotic marker protein.
Prognostic significance:
• High Cas3 expression: Associated with good prognosis and increased sensitivity to chemotherapy in breast, gastric, lung, and pancreatic cancers.
• Low Cas3 expression: Linked to poor prognosis and increased risk of recurrence in colorectal, hepatocellular carcinoma, ovarian, and prostate cancers.
Scientific Papers found: Click to Expand⟱
6492- Nimb,    Review on Molecular and Chemopreventive Potential of Nimbolide in Cancer
- Review, NA, NA
Apoptosis↑, TumCCA↑, TumCP↓, TumCI↓, angioG↓, TumMeta↓, PTEN↑, NF-kB↓, Wnt↓, β-catenin/ZEB1↓, IKKα↓, CXCR2↓, CXCR4↓, Bcl-2↓, COX2↓, MMP9↓, VEGF↓, TIMP2↑, chemoPv↑, ROS↑, DR4↑, P53↑, BAX↑, Casp3↑, Casp8↑, Casp9↑, cl‑PARP↑, Mcl-1↓, XIAP↓, survivin↓, FasL↑, FADD↑, EGFR↓, MMPs↓,
6490- Nimb,    Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer
- in-vitro, Oral, SCC4
PI3K↓, Akt↓, GSK‐3β↑, MMP↓, Apoptosis↑, Bax:Bcl2↑, Cyt‑c↑, cl‑Casp3↑, cl‑Casp9↑, TumAuto↑, Beclin-1↓, p62↑, PI3K↓, chemoPv↑,
6489- Nimb,    Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model
- in-vivo, Pca, DU145 - in-vivo, Pca, LNCaP
tumCV↓, Apoptosis↑, TumCI↓, TumCMig↓, STAT3↓, ROS↑, TumCG↓, TumMeta↓, TumCCA↑, DNAdam↑, Casp3↑, Casp7↑, cl‑PARP↑, p‑STAT3↓, IL6↓, GSR↓,
946- Nimb,    Nimbolide retards T cell lymphoma progression by altering apoptosis, glucose metabolism, pH regulation, and ROS homeostasis
- in-vivo, NA, NA
Apoptosis↑, Bcl-2↓, P53↑, cl‑Casp3↑, Cyt‑c↑, ROS↑, SOD↓, Catalase↓, Glycolysis↓, GLUT3↓, LDHA↓, MCT1↓, NHE1↓, ATPase↓, CAIX↓,
4977- Nimb,    Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis
- vitro+vivo, PC, AsPC-1 - in-vitro, PC, PANC1
SOD2↑, TumCG↓, TumMeta↓, ROS↑, Apoptosis↑, PI3K↓, Akt↓, EMT↓, BAX↑, cl‑Casp3↑, cl‑Casp8↑, cl‑PARP↑, Bcl-2↓,
4976- Nimb,    Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition
- vitro+vivo, PC, NA
ROS↑, Apoptosis↑, TumAuto↑, TumCP↓, TumCMig↓, TumCI↓, EMT↓, Dose↓, selectivity↑, Akt↓, eff↓, BAX↑, cl‑Casp3↑, cl‑PARP↑, Bcl-2↓,

Showing Research Papers: 1 to 6 of 6

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Catalase↓, 1,   GSR↓, 1,   ROS↑, 5,   SOD↓, 1,   SOD2↑, 1,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 1,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

CAIX↓, 1,   Glycolysis↓, 1,   LDHA↓, 1,  

Cell Death ⓘ

Akt↓, 3,   Apoptosis↑, 6,   BAX↑, 3,   Bax:Bcl2↑, 1,   Bcl-2↓, 4,   Casp3↑, 2,   cl‑Casp3↑, 4,   Casp7↑, 1,   Casp8↑, 1,   cl‑Casp8↑, 1,   Casp9↑, 1,   cl‑Casp9↑, 1,   Cyt‑c↑, 2,   DR4↑, 1,   FADD↑, 1,   FasL↑, 1,   Mcl-1↓, 1,   MCT1↓, 1,   survivin↓, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

Autophagy & Lysosomes ⓘ

Beclin-1↓, 1,   p62↑, 1,   TumAuto↑, 2,  

DNA Damage & Repair ⓘ

DNAdam↑, 1,   P53↑, 2,   cl‑PARP↑, 4,  

Cell Cycle & Senescence ⓘ

TumCCA↑, 2,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 2,   GSK‐3β↑, 1,   PI3K↓, 3,   PTEN↑, 1,   STAT3↓, 1,   p‑STAT3↓, 1,   TumCG↓, 2,   Wnt↓, 1,  

Migration ⓘ

ATPase↓, 1,   MMP9↓, 1,   MMPs↓, 1,   TIMP2↑, 1,   TumCI↓, 3,   TumCMig↓, 2,   TumCP↓, 2,   TumMeta↓, 3,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   EGFR↓, 1,   VEGF↓, 1,  

Barriers & Transport ⓘ

GLUT3↓, 1,   NHE1↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   CXCR2↓, 1,   CXCR4↓, 1,   IKKα↓, 1,   IL6↓, 1,   NF-kB↓, 1,  

Drug Metabolism & Resistance ⓘ

Dose↓, 1,   eff↓, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

EGFR↓, 1,   IL6↓, 1,  

Functional Outcomes ⓘ

chemoPv↑, 2,  
Total Targets: 71

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Casp3, CPP32, Cysteinyl aspartate specific proteinase-3
6 Nimbolide
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#:250  Target#:42  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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