Phenylbutyrate / HDAC Cancer Research Results

PB, Phenylbutyrate: Click to Expand ⟱
Features:
Used to treat urea cycle disorders
Sodium phenylbutyrate helps remove ammonia from the body.
-Phenyl-butyrate (PB)4 is an aromatic fatty acid that is converted in vivo to phenylacetate (PA) by β-oxidation in liver and kidney mitochondria.
-In human body, phenylbutyrate is oxidized to phenylacetate, which is in turn conjugated with glutamine and eliminated in urine as phenylacetylglutamine, thereby mediating elimination of waste nitrogen
-Phenylbutyrate is one of the first drugs encountered in cancer therapy as a histone deacetylase inhibitor (HDACI) (relatively weak compared to vorinostat (SAHA), romidepsin, etc.).
-Butyric acid is one of the short-chain fatty acids produced by the gut microbiota through the fermentation of dietary fiber. Butyrate is primarily recognized for its beneficial effects in the colon and is tightly linked to gut health.
-Phenylbutyrate is a derivative of butyrate that has been chemically modified by the addition of a phenyl group. This structural change increases its lipophilicity (fat solubility) and alters its metabolic fate and biological activity. This allows it to be used as a systemic drug, in contrast to the locally produced butyrate in the gut, which is rapidly metabolized by colonocytes

Pathways:
-Histone deacetylase (HDAC) inhibitor
-ER stress inhibitor (at least in normal cell)
-Can act as a chemical chaperone, helping to reduce ER stress by facilitating proper protein folding.
-Modulation of NF-κB Signaling
-Changes in pathways such as PI3K/Akt/mTOR and MAPK.
-Some preclinical investigations have reported that treatment with phenylbutyrate leads to mitochondrial dysfunction and endoplasmic reticulum (ER) stress, both of which can result in an increase of ROS within cancer cells.

Note: Sodium butyrate (NaBu) vs Sodium phenylbutyrate
-Sodium butyrate is primarily a research tool with limited clinical application, whereas phenylbutyrate is used clinically
-Phenylbutyrate typically exhibits improved pharmacokinetics and is more amenable to systemic use compared to sodium butyrate.
-Both compounds act as HDAC inhibitors, phenylbutyrate additionally modulates ER stress and mitochondrial function, leading to potentially greater ROS production in certain cancer cells.

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Rank Pathway / Axis Cancer Context Normal Tissue Context TSF Primary Effect Notes
1 Histone Deacetylase (HDAC) inhibition Histone acetylation ↑; p21 ↑; differentiation ↑; proliferation ↓ Gene-expression modulation R, G Epigenetic reprogramming Core anticancer mechanism; early-generation, relatively weak HDAC inhibitor.
2 Cell-cycle arrest G1 arrest ↑; Cyclin D1 ↓ (reported) ↔ G Cytostasis Common downstream effect of HDAC inhibition.
3 Apoptosis Caspase activation ↑ (reported; model-dependent) ↔ G Cell death execution Often secondary to transcriptional changes and stress modulation.
4 ER stress / Chemical chaperone activity Context-dependent: ER stress ↑ or ↓ ER stress ↓ (protein misfolding disorders) R, G Protein-folding modulation Acts as chemical chaperone; effect depends on cell type and dose.
5 NF-κB signaling NF-κB modulation (reported) Inflammatory tone modulation R, G Transcriptional regulation Likely secondary to epigenetic changes.
6 PI3K → AKT / MAPK pathways Survival pathway modulation (reported; model-dependent) ↔ R, G Growth signaling modulation Downstream transcriptional effects rather than primary kinase inhibition.
7 Mitochondrial stress / ROS ROS modulation (context-dependent) ↔ P, R, G Metabolic adaptation Not a primary ROS-inducing agent; effects vary by tumor model.
8 Urea-cycle nitrogen scavenging (approved indication) — Ammonia elimination ↑ (phenylacetylglutamine formation) — Clinical metabolic role Primary approved medical use.


HDAC, Histone deacetylases: Click to Expand ⟱
Source:
Type:
Enzymes involved in regulating gene expression by removing acetyl groups from histones, the proteins around which DNA is wrapped.
-Many cancers exhibit altered expression levels of HDACs, which can contribute to the dysregulation of genes involved in cell growth, survival, and differentiation.
-HDACs can repress the expression of tumor suppressor genes, leading to uncontrolled cell proliferation and survival. This repression can be a key factor in the development and progression of cancer.
-HDAC inhibitors (HDACi) have been developed and are being investigated for their ability to reactivate silenced genes, induce cell cycle arrest, and promote apoptosis in cancer cells.
-HDAC1, HDAC2): Often overexpressed in various cancers, including breast, prostate, and colorectal cancers. Their overexpression is associated with poor prognosis.
-HDAC4, HDAC5): These may have both oncogenic and tumor-suppressive roles depending on the context and cancer type.
-While HDACs are not classified as traditional oncogenes, their overexpression and activity can contribute to oncogenic processes.
-HDAC inhibitor works by preventing the removal of acetyl groups from histones, thereby modulating gene expression, influencing cell behavior, and potentially reversing aberrant gene silencing seen in various diseases.
-HDAC inhibitors can help reactivate these genes, thereby inhibiting growth and inducing apoptosis in cancer cells.
Scientific Papers found: Click to Expand⟱
2067- PB,    Histone Deacetylase (HDAC) Inhibitors: Current Evidence for Therapeutic Activities in Pancreatic Cancer
- in-vitro, PC, NA
HDAC↓, HATs↑,
2054- PB,    Sodium butyrate induces ferroptosis in endometrial cancer cells via the RBM3/SLC7A11 axis
- in-vitro, EC, ISH - in-vitro, EC, HEC1B
Ferroptosis↑, xCT↓, RBM3↑, HDAC↓, ROS↑,
2061- PB,  Chemo,    Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells
- in-vitro, PC, PANC1 - in-vitro, PC, COLO357 - in-vitro, PC, Bxpc-3
HDAC↓, Apoptosis↑, eff↑, selectivity↑, TumCCA↑, eff↑, selectivity↑,
2064- PB,  Rad,    Phenylbutyrate Attenuates the Expression of Bcl-XL, DNA-PK, Caveolin-1, and VEGF in Prostate Cancer Cells
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145 - in-vitro, Pca, LNCaP
Bcl-xL↓, Cav1↓, VEGF↓, RadioS↑, chemoP↑, HDAC↓, *toxicity↓, Diff↑, Prot↓,
2074- PB,  Chemo,    The effect of combined treatment with sodium phenylbutyrate and cisplatin, erlotinib, or gefitinib on resistant NSCLC cells
- in-vitro, Lung, A549 - in-vitro, Lung, Calu-6 - in-vitro, Lung, H1650
TumCG↓, eff↑, ChemoSen↑, HDAC↓,
2075- PB,  Chemo,    Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Colorectal Cancer after Failure of Second-Line Therapy—A Potential Strategy for Improved Survival
- Trial, CRC, NA
OS↑, HDAC↓,
2077- PB,    Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells
- in-vitro, Liver, HUH7
miR-22↑, SIRT1↓, ROS↑, Cyt‑c↑, Casp3↑, eff↓, TumCG↓, TumCP↓, HDAC↓, SIRT1↓, CD44↓, proMMP2↓, MMP↓, SOD↓,
2052- PB,    Lipid-regulating properties of butyric acid and 4-phenylbutyric acid: Molecular mechanisms and therapeutic applications
- Review, NA, NA
*HDAC↓, *Half-Life↑, *Half-Life↑, *lipoGen↓, *ER Stress↓, *FAO↑, *ROS↓, *BioAv↑,
998- PB,    Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti-cancer effect
- in-vivo, NA, NA
p‑PDH↓, PDH↑, PDK1↓, HDAC↓, Glycolysis↓, MMP↓, Apoptosis↑,
2026- PB,    Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study
- Trial, GBM, NA
Dose↝, Dose↑, Dose↝, OS↑, HDAC↓, TumCCA↑, P21↑, other↝, BioAv↑, eff↑,
2027- PB,    Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors
- Trial, Var, NA
TumCG↓, Dose↝, toxicity↓, Dose↝, HDAC↓, OS↑,
2028- PB,    Potential of Phenylbutyrate as Adjuvant Chemotherapy: An Overview of Cellular and Molecular Anticancer Mechanisms
- Review, Var, NA
HDAC↓, TumCCA↑, P21↑, Dose↝, Telomerase↓, IGFBP3↑, p‑p38↑, JNK↑, ERK↑, BAX↑, Casp3↑, Bcl-2↓, Cyt‑c↝, FAK↓, survivin↓, VEGF↓, angioG↓, DNArepair↓, TumMeta↓, HSP27↑, ASK1↑, ROS↑, eff↑, ER Stress↓, GRP78/BiP↓, CHOP↑, AR↓, other?,
2029- PB,    Phenylbutyric Acid: simple structure - multiple effects
- Review, Var, NA
NH3↓, HDAC↓, ChemChap↑,
2030- PB,    4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor
- Review, Nor, NA
*HDAC↓, *neuroP↑, *ChemChap↑,
2031- PB,    Phenylbutyrate is a multifaceted drug that exerts neuroprotective effects and reverses the Alzheimer´s disease-like phenotype of a commonly used mouse model
- in-vivo, AD, NA
*neuroP↑, *HDAC↓, *ChemChap↑,
2035- PB,    Sodium Phenylbutyrate Controls Neuroinflammatory and Antioxidant Activities and Protects Dopaminergic Neurons in Mouse Models of Parkinson’s Disease
- in-vitro, Nor, glial - in-vivo, NA, NA
*ROS↓, *Inflam↑, *P21↓, *antiOx↑, *GSH↑, *NF-kB↓, *neuroP↑, *HDAC↓, *iNOS↓, *TNF-α↓, *IL1β↓, *LDL↓, ROS↓,
2039- PB,    TXNIP mediates the differential responses of A549 cells to sodium butyrate and sodium 4‐phenylbutyrate treatment
- in-vitro, Lung, A549 - in-vitro, Nor, HEK293
TXNIP↑, Casp3↑, Casp7↑, mt-ROS↑, GlucoseCon↓, TumCP↓, TumCD↑, IGF-2↑, HDAC↓, ROS⇅,
2042- PB,    Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury
- in-vitro, Nor, NA
*HDAC↓, *toxicity↓, *LDH↓, *SOD2↑, *ROS↓, *cardioP↑, *antiOx↑,
2043- PB,  Cisplatin,    Phenylbutyrate interferes with the Fanconi anemia and BRCA pathway and sensitizes head and neck cancer cells to cisplatin
- in-vitro, HNSCC, UM-SCC-1
ChemoSen↑, eff↑, HDAC↓, BRCA1↓, RadioS↑,
2045- PB,    Phenylbutyrate—a pan-HDAC inhibitor—suppresses proliferation of glioblastoma LN-229 cell line
- in-vitro, GBM, LN229 - in-vitro, GBM, LN-18
HDAC↓, TumCG↓, TumCCA↑, P21↑, Bcl-2↓, Bcl-xL↓, BioAv↑,
2046- PB,    Sodium butyrate promotes apoptosis in breast cancer cells through reactive oxygen species (ROS) formation and mitochondrial impairment
- in-vitro, BC, MCF-7 - in-vitro, BC, MDA-MB-468 - in-vitro, Nor, MCF10
Apoptosis↑, i-ROS?, Casp↑, MMP?, selectivity↑, *ROS∅, HDAC↓, DNArepair↓, Casp3↑, Casp8↑, *toxicity↓, TumCCA↑,
2048- PB,    Sodium Phenylbutyrate Inhibits Tumor Growth and the Epithelial-Mesenchymal Transition of Oral Squamous Cell Carcinoma In Vitro and In Vivo
- in-vitro, OS, CAL27 - in-vitro, Oral, HSC3 - in-vitro, OS, SCC4 - in-vivo, NA, NA
*NH3↓, *HDAC↓, *ER Stress↓, Apoptosis?, Bcl-2↓, cl‑Casp3↑, TGF-β↑, N-cadherin↓, E-cadherin↑, TumVol↓, eff↑,
2049- PB,    Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors
- Review, Var, NA
HDAC↓, ac‑H3↑, ac‑H4↑, ac‑H3↑, eff↝, toxicity↓,

Showing Research Papers: 1 to 23 of 23

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 23

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 1,   ROS↓, 1,   ROS↑, 3,   ROS⇅, 1,   i-ROS?, 1,   mt-ROS↑, 1,   SOD↓, 1,   xCT↓, 1,  

Mitochondria & Bioenergetics ⓘ

MMP?, 1,   MMP↓, 2,  

Core Metabolism/Glycolysis ⓘ

Cav1↓, 1,   GlucoseCon↓, 1,   Glycolysis↓, 1,   NH3↓, 1,   PDH↑, 1,   p‑PDH↓, 1,   PDK1↓, 1,   SIRT1↓, 2,  

Cell Death ⓘ

Apoptosis?, 1,   Apoptosis↑, 3,   ASK1↑, 1,   BAX↑, 1,   Bcl-2↓, 3,   Bcl-xL↓, 2,   Casp↑, 1,   Casp3↑, 4,   cl‑Casp3↑, 1,   Casp7↑, 1,   Casp8↑, 1,   Cyt‑c↑, 1,   Cyt‑c↝, 1,   Ferroptosis↑, 1,   JNK↑, 1,   p‑p38↑, 1,   survivin↓, 1,   Telomerase↓, 1,   TumCD↑, 1,  

Transcription & Epigenetics ⓘ

ac‑H3↑, 2,   ac‑H4↑, 1,   HATs↑, 1,   other?, 1,   other↝, 1,   Prot↓, 1,  

Protein Folding & ER Stress ⓘ

ChemChap↑, 1,   CHOP↑, 1,   ER Stress↓, 1,   GRP78/BiP↓, 1,   HSP27↑, 1,  

DNA Damage & Repair ⓘ

BRCA1↓, 1,   DNArepair↓, 2,  

Cell Cycle & Senescence ⓘ

P21↑, 3,   TumCCA↑, 5,  

Proliferation, Differentiation & Cell State ⓘ

CD44↓, 1,   Diff↑, 1,   ERK↑, 1,   HDAC↓, 17,   IGF-2↑, 1,   IGFBP3↑, 1,   TumCG↓, 4,  

Migration ⓘ

E-cadherin↑, 1,   FAK↓, 1,   miR-22↑, 1,   proMMP2↓, 1,   N-cadherin↓, 1,   TGF-β↑, 1,   TumCP↓, 2,   TumMeta↓, 1,   TXNIP↑, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   VEGF↓, 2,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 2,   ChemoSen↑, 2,   Dose↑, 1,   Dose↝, 5,   eff↓, 1,   eff↑, 7,   eff↝, 1,   RadioS↑, 2,   selectivity↑, 3,  

Clinical Biomarkers ⓘ

AR↓, 1,   BRCA1↓, 1,   RBM3↑, 1,  

Functional Outcomes ⓘ

chemoP↑, 1,   OS↑, 3,   toxicity↓, 2,   TumVol↓, 1,  
Total Targets: 87

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 2,   GSH↑, 1,   ROS↓, 3,   ROS∅, 1,   SOD2↑, 1,  

Core Metabolism/Glycolysis ⓘ

FAO↑, 1,   LDH↓, 1,   LDL↓, 1,   lipoGen↓, 1,   NH3↓, 1,  

Cell Death ⓘ

iNOS↓, 1,  

Protein Folding & ER Stress ⓘ

ChemChap↑, 2,   ER Stress↓, 2,  

Cell Cycle & Senescence ⓘ

P21↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

HDAC↓, 6,  

Immune & Inflammatory Signaling ⓘ

IL1β↓, 1,   Inflam↑, 1,   NF-kB↓, 1,   TNF-α↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 1,   Half-Life↑, 2,  

Clinical Biomarkers ⓘ

LDH↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   neuroP↑, 3,   toxicity↓, 3,  
Total Targets: 25

Scientific Paper Hit Count for: HDAC, Histone deacetylases
23 Phenylbutyrate
3 Chemotherapy
1 Radiotherapy/Radiation
1 Cisplatin
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#:15  Target#:140  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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