Nimbolide / P21 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
P21, P21/CDKN1A: Click to Expand ⟱
Source:
Type: Proapototic
cyclin-dependent kinase inhibitor p21 (also known as p21 WAF1/Cip1) promotes cell cycle arrest in response to many stimuli.
P21 is a cyclin-dependent kinase inhibitor that plays a crucial role in regulating the cell cycle. It is encoded by the CDKN1A gene and is a key player in the cellular response to stress, including DNA damage.
P21 is often considered a tumor suppressor because its expression is upregulated in response to p53 activation, a well-known tumor suppressor protein. When DNA damage occurs, p53 can activate the transcription of the CDKN1A gene, leading to increased levels of P21, which helps prevent the proliferation of damaged cells.
In many cancers, the p53 pathway is disrupted, leading to decreased levels of P21. p21 is a apoptotic marker protein.
Cell cycle arrest gene p21
Field Suggested Entry
Target CDKN1A / p21 / p21Cip1/Waf1
Full Name Cyclin-dependent kinase inhibitor 1A
Target Class CIP/KIP-family cyclin-dependent kinase inhibitor
Main Binding Partners CDK2, CDK1, CDK4/6, cyclin complexes, PCNA
Primary Biology p53-mediated cell-cycle arrest, DNA damage response, senescence, differentiation, CDK inhibition, RB/E2F pathway suppression, apoptosis regulation
Cancer Relevance High but context-dependent: p21 can suppress tumor growth through cell-cycle arrest and senescence, but can also support apoptosis resistance, senescent-cell survival, and therapy resistance in some tumors
AD Relevance Medium: indirect relevance through neuronal cell-cycle re-entry, senescence, p53 stress signaling, and aging-related cell-cycle dysregulation
Therapeutic Direction Context-dependent. Restore/activate p21 for tumor-suppressive arrest where appropriate; inhibit or bypass p21 where it promotes apoptosis resistance, senescent-cell survival, or treatment resistance.


Scientific Papers found: Click to Expand⟱
6486- Nimb,    Nimbolide: promising agent for prevention and treatment of chronic diseases
- Review, Var, NA - Review, AD, NA
*other↝, *Inflam↓, AntiCan↑, *Bacteria↓, *AntiViral↑, *neuroP↑, *hepatoP↑, *ROS?, *NRF2↑, *HO-1↑, *TLR4↓, *NF-kB↓, *AChE↓, *Aβ↓, *GSK‐3β↓, *LDL↓, *DNAdam↓, *lipid-P↓, *antiOx↑, *SOD1↑, *GSH↑, *IL6↓, *IL1β↓, *STAT3↓, *GPx↑, *Catalase↑, *MDA↓, *AntiDiabetic↑, *HDL↓, *MCP1↓, *VEGF↓, *MMP9↓, *GutMicro↑, TumCP↓, TumCCA↑, TumCMig↓, NF-kB↓, ROS↑, PI3K↓, Akt↓, mTOR↓, ERK↓, EMT↓, TumMeta↓, ChemoSen↑, eff↑, selectivity↑, CDK4↓, CDK6↓, Wnt↓, β-catenin/ZEB1↓, STAT3↓, MMP2↓, Sp1/3/4↓, AP-1↓, P21↑, *AntiArt↑, *IL23↓, *IL17↓, *IFN-γ↓, *HSP70/HSPA5↓,

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:


Redox & Oxidative Stress ⓘ

ROS↑, 1,  

Cell Death ⓘ

Akt↓, 1,  

Kinase & Signal Transduction ⓘ

Sp1/3/4↓, 1,  

Cell Cycle & Senescence ⓘ

CDK4↓, 1,   P21↑, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,   ERK↓, 1,   mTOR↓, 1,   PI3K↓, 1,   STAT3↓, 1,   Wnt↓, 1,  

Migration ⓘ

AP-1↓, 1,   MMP2↓, 1,   TumCMig↓, 1,   TumCP↓, 1,   TumMeta↓, 1,   β-catenin/ZEB1↓, 1,  

Immune & Inflammatory Signaling ⓘ

NF-kB↓, 1,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   eff↑, 1,   selectivity↑, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,  
Total Targets: 24

Pathway results for Effect on Normal Cells:


NA, unassigned ⓘ

AntiArt↑, 1,  

Redox & Oxidative Stress ⓘ

antiOx↑, 1,   Catalase↑, 1,   GPx↑, 1,   GSH↑, 1,   HDL↓, 1,   HO-1↑, 1,   lipid-P↓, 1,   MDA↓, 1,   NRF2↑, 1,   ROS?, 1,   SOD1↑, 1,  

Core Metabolism/Glycolysis ⓘ

LDL↓, 1,  

Transcription & Epigenetics ⓘ

other↝, 1,  

Protein Folding & ER Stress ⓘ

HSP70/HSPA5↓, 1,  

DNA Damage & Repair ⓘ

DNAdam↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

GSK‐3β↓, 1,   STAT3↓, 1,  

Migration ⓘ

MMP9↓, 1,  

Angiogenesis & Vasculature ⓘ

VEGF↓, 1,  

Immune & Inflammatory Signaling ⓘ

IFN-γ↓, 1,   IL17↓, 1,   IL1β↓, 1,   IL23↓, 1,   IL6↓, 1,   Inflam↓, 1,   MCP1↓, 1,   NF-kB↓, 1,   TLR4↓, 1,  

Synaptic & Neurotransmission ⓘ

AChE↓, 1,  

Protein Aggregation ⓘ

Aβ↓, 1,  

Clinical Biomarkers ⓘ

GutMicro↑, 1,   IL6↓, 1,  

Functional Outcomes ⓘ

AntiDiabetic↑, 1,   hepatoP↑, 1,   neuroP↑, 1,  

Infection & Microbiome ⓘ

AntiViral↑, 1,   Bacteria↓, 1,  
Total Targets: 38

Scientific Paper Hit Count for: P21, P21/CDKN1A
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#:234  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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