Cisplatin / LDH Cancer Research Results

Cisplatin, Cisplatin: Click to Expand ⟱
Features:
Cisplatin is a chemotherapy medication used to treat various types of cancer. It is a platinum-based drug that works by interfering with the DNA of cancer cells, preventing them from reproducing and ultimately leading to cell death.
Cisplatin (cis-diamminedichloroplatinum II; CDDP) is a platinum-based chemotherapeutic agent that forms covalent DNA crosslinks, primarily intrastrand adducts at adjacent guanine bases. These distort DNA structure, block replication and transcription, and activate DNA damage response pathways (ATM/ATR → p53), leading to cell-cycle arrest and apoptosis. Secondary mechanisms include ROS generation, stress MAPK activation, and modulation of NF-κB. Clinical resistance frequently involves enhanced DNA repair (ERCC1/NER), altered drug transport (CTR1, ATP7A/B), and increased antioxidant defenses. Major toxicities include nephrotoxicity, ototoxicity, and peripheral neuropathy.

Rank Pathway / Axis Cancer / Tumor Context Normal Tissue Context TSF Primary Effect Notes / Interpretation
1 DNA crosslink formation (intrastrand adducts) DNA adducts ↑; replication block ↑ Normal dividing cells also affected P, R, G Direct DNA cytotoxicity Cisplatin forms covalent intrastrand crosslinks (primarily at adjacent guanines), distorting DNA and blocking replication and transcription.
2 DNA damage response (ATM / ATR → p53) Checkpoint activation ↑; p53 signaling ↑ ↔ (toxicity in proliferating tissues) R, G Damage signaling cascade DNA distortion activates ATM/ATR pathways leading to p53-mediated cell-cycle arrest and apoptosis.
3 Intrinsic apoptosis (mitochondrial pathway) Bax ↑; Bcl-2 ↓; caspase-9/3 ↑ Nephrotoxicity & ototoxicity risk G Execution of cell death Persistent DNA damage triggers mitochondrial outer membrane permeabilization and caspase activation.
4 Cell-cycle arrest (G2/M emphasis) G2/M arrest ↑ ↔ G Cytostasis → apoptosis Cells accumulate in G2/M phase due to unrepaired DNA lesions.
5 ROS generation / oxidative stress ROS ↑ (secondary mechanism) Oxidative injury ↑ (kidney, cochlea) R, G Stress amplification Cisplatin increases mitochondrial ROS and oxidative stress, contributing to cytotoxicity and organ toxicity.
6 MAPK signaling (JNK / p38 activation) Stress MAPK activation ↑ ↔ R, G Stress-response signaling JNK and p38 activation contribute to apoptosis and stress signaling.
7 NF-κB activation (resistance axis) NF-κB ↑ may promote survival ↔ R, G Resistance modulation NF-κB activation can reduce sensitivity; inhibition enhances cytotoxicity in some models.
8 DNA repair pathways (NER / ERCC1) NER ↑ → resistance — G Resistance determinant Nucleotide excision repair (ERCC1) removes platinum adducts; high ERCC1 correlates with resistance.
9 Drug transport (CTR1 uptake; ATP7A/B efflux) CTR1 ↓ or ATP7A/B ↑ → resistance — G Exposure constraint Copper transporters influence intracellular cisplatin accumulation and resistance.
10 Clinical toxicity profile — Nephrotoxicity, ototoxicity, neurotoxicity — Translation constraint Major dose-limiting toxicities arise from DNA damage and oxidative stress in normal tissues.

Time-Scale Flag (TSF): P / R / G

  • P: 0–30 min (DNA aquation and initial adduct formation)
  • R: 30 min–3 hr (checkpoint activation / stress signaling)
  • G: >3 hr (apoptosis, phenotype outcomes, resistance development)
LDH, Lactate Dehydrogenase: Click to Expand ⟱
Source:
Type:
LDH is a general term that refers to the enzyme that catalyzes the interconversion of lactate and pyruvate. LDH is a tetrameric enzyme, meaning it is composed of four subunits.
LDH refers to the enzyme as a whole, while LDHA specifically refers to the M subunit. Elevated LDHA levels are often associated with poor prognosis and aggressive tumor behavior, similar to elevated LDH levels.
leakage of LDH is a well-known indicator of cell membrane integrity and cell viability [35]. LDH leakage results from the breakdown of the plasma membrane and alterations in membrane permeability, and is widely used as a cytotoxicity endpoint.

However, it's worth noting that some studies have shown that LDHA is a more specific and sensitive biomarker for cancer than total LDH, as it is more closely associated with the Warburg effect and cancer metabolism.

Dysregulated LDH activity contributes significantly to cancer development, promoting the Warburg effect (Chen et al., 2007), which involves increased glucose uptake and lactate production, even in the presence of oxygen, to meet the energy demands of rapidly proliferating cancer cells (Warburg and Minami, 1923; Dai et al., 2016b). LDHA overexpression favors pyruvate to lactate conversion, leading to tumor microenvironment acidification and aiding cancer progression and metastasis.

Inhibitors:
Flavonoids, a group of polyphenols abundant in fruit, vegetables, and medicinal plants, function as LDH inhibitors.
LDH is used as a clinical biomarker for Synthetic liver function, nutrition

Tier A — Direct LDH Enzyme Inhibitors (Validated Catalytic Inhibition)

Rank Compound Type LDH Target Potency Level Primary Effect Notes
1 NCI-006 Research drug LDHA / LDHB High (in vivo active) Potent glycolysis suppression Modern benchmark LDH inhibitor used in metabolic oncology models.
2 (R)-GNE-140 Research drug LDHA (±LDHB) High (nM range reported) Lactate production ↓ Widely used experimental LDH inhibitor.
3 FX11 Research drug LDHA High (μM range) Metabolic crisis in LDHA-dependent tumors Classic LDHA inhibitor; often increases ROS secondary to metabolic stress.
4 Oxamate Tool compound LDH (pyruvate-competitive) Moderate (mM cellular use) Reduces lactate flux Classical LDH inhibitor; requires high concentrations in cells.
5 Gossypol Natural product derivative LDHA Moderate–High Glycolysis inhibition Also has other targets; safety considerations apply.
6 Galloflavin Natural compound LDH isoforms Moderate Lactate production ↓ One of the better-supported “natural-like” LDH inhibitors.

Tier B — Indirect LDH-Axis Modulators (Glycolysis / Lactate Reduction Without Confirmed Direct Catalytic Inhibition)

Rank Compound Mechanism Type LDH Claim Type Primary Axis Notes / Caution
1 Lonidamine MCT/MPC modulation Lactate axis inhibition Metabolic transport blockade Better classified as lactate/pyruvate transport modulator.
2 Stiripentol Repurposed drug LDH pathway modulation Metabolic axis modulation Emerging oncology interest; primarily neurological drug.
3 Quercetin Flavonoid Reported LDH inhibition (mixed evidence) NF-κB / PI3K modulation Often LDH-release confusion; direct enzymatic proof limited.
4 Ursolic acid Triterpenoid Reported LDH interaction Warburg modulation More credible as metabolic signaling modulator.
5 Fisetin Flavonoid Docking / indirect reports Apoptosis / survival signaling Enzyme inhibition not well validated.
6 Resveratrol Polyphenol Indirect glycolysis suppression AMPK / HIF-1α modulation Reduces lactate via upstream signaling.
7 Curcumin Polyphenol Indirect LDH expression modulation Inflammation + metabolic signaling Bioavailability limits translational strength.
8 Berberine Alkaloid Indirect metabolic modulation AMPK activation Closer to metformin-like metabolic pressure.
9 Honokiol Lignan Indirect glycolysis effects Survival pathway suppression Not validated as catalytic LDH inhibitor.
10 Silibinin Flavonolignan Mixed / indirect reports Inflammation + metabolic axis Often misclassified as LDH inhibitor.
11 Kaempferol Flavonoid Often LDH-release marker confusion Glucose transport / signaling Do not list as direct LDH inhibitor without enzyme data.
12 Oleanolic acid / Limonin / Allicin / Taurine Natural compounds Weak / indirect evidence General metabolic modulation Should not be categorized as true LDH inhibitors.

Tier A = Direct catalytic LDH inhibition (enzyme-level validation).
Tier B = Indirect lactate reduction or glycolytic modulation without strong catalytic inhibition evidence.
Important: LDH release assays (cell damage marker) are not proof of LDH enzymatic inhibition.



Scientific Papers found: Click to Expand⟱
6333- Eug,  Cisplatin,  Rad,    Eugenol Exerts Apoptotic Effect and Modulates the Sensitivity of HeLa Cells to Cisplatin and Radiation
- in-vitro, Cerv, HeLa
TumCP↓, LDH↝, ChemoSen↑, RadioS↑, Casp3↑, BAX↑, Cyt‑c↑, Casp9↑, Bcl-2↓, COX2↓, IL1β↓, ROS↑, NF-kB↓, COX2↓, TumCCA↓, Thiols↓, GSH↓,

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 ⓘ

GSH↓, 1,   ROS↑, 1,   Thiols↓, 1,  

Core Metabolism/Glycolysis ⓘ

LDH↝, 1,  

Cell Death ⓘ

BAX↑, 1,   Bcl-2↓, 1,   Casp3↑, 1,   Casp9↑, 1,   Cyt‑c↑, 1,  

Cell Cycle & Senescence ⓘ

TumCCA↓, 1,  

Migration ⓘ

TumCP↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   IL1β↓, 1,   NF-kB↓, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   RadioS↑, 1,  

Clinical Biomarkers ⓘ

LDH↝, 1,  
Total Targets: 17

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: LDH, Lactate Dehydrogenase
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#:197  Target#:906  State#:%  Dir#:4
  wNotes=0  sortOrder:rid,rpid

 

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