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⟱
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↓,

Showing Research Papers: 1 to 3 of 3

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress

ROS↑, 1,  

Mitochondria & Bioenergetics

MMP↓, 1,  

Cell Death

Apoptosis↑, 2,   BID↑, 1,   pro‑Casp12↓, 1,   Casp3↑, 1,   Casp7↑, 1,   p38↑, 1,   TumCD↑, 1,  

Transcription & Epigenetics

other↝, 2,  

Protein Folding & ER Stress

CHOP↑, 2,   ER Stress↑, 3,   GRP78/BiP↑, 1,   HSP27↓, 1,   IRE1↓, 1,  

Autophagy & Lysosomes

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

Migration

Ca+2↝, 1,   TumCP↓, 1,   TumCP↑, 1,  

Angiogenesis & Vasculature

PDI↑, 1,  

Drug Metabolism & Resistance

eff↑, 1,   eff↝, 1,  
Total Targets: 25

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: ER Stress, endoplasmic reticulum (ER) stress signaling pathway
3 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#:2
wNotes=0 sortOrder:rid,rpid

 

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