Phenylbutyrate / ER Stress 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.


ER Stress, endoplasmic reticulum (ER) stress signaling pathway: Click to Expand ⟱
Source:
Type:
Protein expression of ATF, GRP78, and GADD153 which is a hall marker of ER stress.
The endoplasmic reticulum (ER) stress signaling pathway plays a crucial role in maintaining cellular homeostasis and responding to various stressors, including those encountered in cancer. When cells experience stress, such as the accumulation of misfolded proteins, they activate a series of signaling pathways collectively known as the unfolded protein response (UPR). The UPR aims to restore normal function by enhancing the protein-folding capacity of the ER, degrading misfolded proteins, and, if the stress is unresolved, triggering apoptosis.
The activation of ER stress pathways can contribute to resistance against chemotherapy and targeted therapies. Cancer cells may utilize the UPR to survive treatment-induced stress, making it challenging to achieve effective therapeutic outcomes.

-ER stress-associated proteins include: phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12
Scientific Papers found: Click to Expand⟱
2056- PB,    Endoplasmic Reticulum Stress Induces ROS Production and Activates NLRP3 Inflammasome Via the PERK-CHOP Signaling Pathway in Dry Eye Disease
- in-vitro, Nor, HCE-2
*ROS↓, *NLRP3↓, *IL1β↓, *TXNIP↑, *ER Stress↓,
2057- PB,    Trichomonas vaginalis induces apoptosis via ROS and ER stress response through ER–mitochondria crosstalk in SiHa cells
- in-vitro, Cerv, SiHa
ROS↓, tumCV∅, cl‑PARP↓, cl‑Casp3↓, MMP∅, ER Stress↓,
2058- PB,    Induction of Human-Lung-Cancer-A549-Cell Apoptosis by 4-Hydroperoxy-2-decenoic Acid Ethyl Ester through Intracellular ROS Accumulation and the Induction of Proapoptotic CHOP Expression
- in-vitro, Lung, A549
ER Stress↓,
2065- PB,  TMZ,    Inhibition of Mitochondria- and Endoplasmic Reticulum Stress-Mediated Autophagy Augments Temozolomide-Induced Apoptosis in Glioma Cells
- in-vitro, GBM, NA
eff↑, ROS↑, MMP↓, ER Stress↑, CHOP↑, GRP78/BiP↑, pro‑Casp12↓, eff↝, Ca+2↝,
2076- PB,    Sodium Butyrate Induces Endoplasmic Reticulum Stress and Autophagy in Colorectal Cells: Implications for Apoptosis
- in-vitro, CRC, HCT116 - in-vitro, CRC, HT29
TumCP↓, TumAuto↑, Apoptosis↑, ER Stress↑, BID↑, CHOP↑, PDI↑, IRE1↓, LC3‑Ⅱ/LC3‑Ⅰ↑, LC3B↑, Beclin-1↑, other↝, other↝,
2078- PB,    Butyrate-induced apoptosis in HCT116 colorectal cancer cells includes induction of a cell stress response
- in-vitro, CRC, HCT116
p38↑, ER Stress↑, Casp3↑, Casp7↑, TumCD↑, Apoptosis↑, TumCP↑, HSP27↓,
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↑,
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?,
2034- PB,    Protective effects of 4-phenylbutyrate derivatives on the neuronal cell death and endoplasmic reticulum stress
- in-vitro, Nor, SH-SY5Y
*ER Stress↓, *ChemChap↓, *cytoP↑, *cellD↓, *neuroP↑,
2041- PB,    The Effect of Glucose Concentration and Sodium Phenylbutyrate Treatment on Mitochondrial Bioenergetics and ER Stress in 3T3-L1 Adipocytes
- in-vitro, Nor, 3T3
*mitResp↓, *ER Stress↓, MMP↓, GlucoseCon↓, OCR↓, CHOP↑,
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↑,
2051- PB,    Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium
- in-vivo, Inf, NA
*Inf↓, *GutMicro↑, *IL17↑, *Inflam↓, *ER Stress↓, *ROS↓, *OS↑, *Bacteria↓, *Neut↑, *toxicity↓,
2053- PB,    4-Phenyl butyric acid prevents glucocorticoid-induced osteoblast apoptosis by attenuating endoplasmic reticulum stress
- in-vitro, ostP, 3T3
*ER Stress↓, *mtDam↓, *Apoptosis↓, eff↑,

Showing Research Papers: 1 to 13 of 13

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 13

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

ROS↓, 1,   ROS↑, 2,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 2,   MMP∅, 1,   OCR↓, 1,  

Core Metabolism/Glycolysis ⓘ

GlucoseCon↓, 1,  

Cell Death ⓘ

Apoptosis?, 1,   Apoptosis↑, 2,   ASK1↑, 1,   BAX↑, 1,   Bcl-2↓, 2,   BID↑, 1,   pro‑Casp12↓, 1,   Casp3↑, 2,   cl‑Casp3↓, 1,   cl‑Casp3↑, 1,   Casp7↑, 1,   Cyt‑c↝, 1,   JNK↑, 1,   p38↑, 1,   p‑p38↑, 1,   survivin↓, 1,   Telomerase↓, 1,   TumCD↑, 1,  

Transcription & Epigenetics ⓘ

other?, 1,   other↝, 2,   tumCV∅, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 4,   ER Stress↓, 3,   ER Stress↑, 3,   GRP78/BiP↓, 1,   GRP78/BiP↑, 1,   HSP27↓, 1,   HSP27↑, 1,   IRE1↓, 1,  

Autophagy & Lysosomes ⓘ

Beclin-1↑, 1,   LC3‑Ⅱ/LC3‑Ⅰ↑, 1,   LC3B↑, 1,   TumAuto↑, 1,  

DNA Damage & Repair ⓘ

DNArepair↓, 1,   cl‑PARP↓, 1,  

Cell Cycle & Senescence ⓘ

P21↑, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,   HDAC↓, 1,   IGFBP3↑, 1,  

Migration ⓘ

Ca+2↝, 1,   E-cadherin↑, 1,   FAK↓, 1,   N-cadherin↓, 1,   TGF-β↑, 1,   TumCP↓, 1,   TumCP↑, 1,   TumMeta↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   PDI↑, 1,   VEGF↓, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

Dose↝, 1,   eff↑, 4,   eff↝, 1,  

Clinical Biomarkers ⓘ

AR↓, 1,  

Functional Outcomes ⓘ

TumVol↓, 1,  
Total Targets: 63

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

ROS↓, 3,  

Mitochondria & Bioenergetics ⓘ

mitResp↓, 1,   mtDam↓, 1,  

Core Metabolism/Glycolysis ⓘ

FAO↑, 1,   lipoGen↓, 1,   NH3↓, 1,  

Cell Death ⓘ

Apoptosis↓, 1,   cellD↓, 1,  

Protein Folding & ER Stress ⓘ

ChemChap↓, 1,   ER Stress↓, 7,  

Proliferation, Differentiation & Cell State ⓘ

HDAC↓, 2,  

Migration ⓘ

TXNIP↑, 1,  

Immune & Inflammatory Signaling ⓘ

IL17↑, 1,   IL1β↓, 1,   Inflam↓, 1,   Neut↑, 1,  

Protein Aggregation ⓘ

NLRP3↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 1,   Half-Life↑, 2,  

Clinical Biomarkers ⓘ

GutMicro↑, 1,  

Functional Outcomes ⓘ

cytoP↑, 1,   neuroP↑, 1,   OS↑, 1,   toxicity↓, 1,  

Infection & Microbiome ⓘ

Bacteria↓, 1,   Inf↓, 1,  
Total Targets: 26

Scientific Paper Hit Count for: ER Stress, endoplasmic reticulum (ER) stress signaling pathway
13 Phenylbutyrate
1 temozolomide
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#:103  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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