methylseleninic acid Cancer Research Results

MeSA, methylseleninic acid: Click to Expand ⟱
Features:
Methylseleninic acid, a widespread selenium-containing compound of organic nature.

Methylseleninic acid — Methylseleninic acid is a monomethylated organoselenium small molecule and experimental selenium-based anticancer/chemopreventive agent that functions as a proximal precursor of methylselenol without requiring β-lyase activation. It is commonly abbreviated MSeA or MSA; MeSA is also used but is potentially ambiguous with methyl salicylate. MSeA is primarily an experimental compound rather than a dietary selenium form or approved drug. It is chemically and biologically related to Se-methylselenocysteine, but the two compounds are not mechanistically interchangeable. Its anticancer activity is strongly concentration-, cell-type-, and redox-context-dependent.

Primary mechanisms (ranked):

  1. Redox/thiol disruption with ROS and lipid-peroxidation increase, oxidation of protein sulfhydryls, and context-dependent GSH depletion, producing oxidative damage preferentially in susceptible cancer cells.
  2. Apoptosis induction through mitochondrial dysfunction, cytochrome-c/caspase activation, ER-stress signaling, CHOP induction, and in some models AIF-associated pathways.
  3. Redox-mediated inhibition/modulation of signaling proteins including PKC isoenzymes, with downstream suppression of proliferative and survival signaling.
  4. Suppression of oncogenic survival pathways including AKT, STAT3, β-catenin, androgen-receptor signaling, and context-dependent ERK signaling.
  5. ER stress and unfolded-protein-response activation involving PERK/eIF2α, GRP78/GRP94 and CHOP, progressing from adaptive stress toward apoptosis at higher exposure.
  6. Suppression of hypoxia/angiogenesis signaling including HIF-1α, VEGF, neuropilin-1 and Ang-2/Tie2-associated signaling.
  7. Cell-cycle inhibition and antiproliferative activity, including G1 or G2/M effects depending on tumor model.
  8. Chemosensitization and radiosensitization, including enhanced responses to paclitaxel, etoposide, docetaxel and ionizing radiation in preclinical models.

Bioavailability / PK relevance: Oral MSeA is systemically absorbed in rodents and increases selenium concentrations in plasma and multiple tissues. It is metabolically useful because it provides a relatively direct route to monomethylated selenium chemistry and methylselenol without the β-lyase requirement of Se-methylselenocysteine. Human MSeA pharmacokinetics, tolerated systemic exposure, and therapeutic plasma concentrations have not been adequately established. Selenium has a comparatively narrow safety margin at pharmacologic exposure, so rodent anticancer doses cannot be directly translated into human dosing.

In-vitro vs systemic exposure relevance: Most direct anticancer experiments use approximately low-micromolar MSeA, commonly around 1–10 µM, although sensitivity varies substantially among models and higher concentrations are sometimes used. Comparable sustained free-MSeA concentrations have not been demonstrated as safely achievable in humans. Consequently, micromolar in-vitro findings should be considered mechanistic/preclinical rather than evidence of clinically achievable drug exposure.

Clinical evidence status: Preclinical. MSeA has substantial cell-culture and animal xenograft/transgenic-model evidence, including chemotherapy and radiation sensitization, but it has not established clinical anticancer efficacy in humans and is not an approved cancer therapy. Recent reviews discussing selenium clinical translation distinguish MSeA from selenium compounds that have actually entered human oncology trials.

Methylseleninic Acid Cancer Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Redox stress and ROS ROS ↑; oxidative damage ↑; lipid peroxidation ↑; GSH ↓ (context-dependent) ROS ↔/↓ or lower susceptibility (model-dependent) P/R/G Pro-oxidant cytotoxicity Central anticancer mechanism in many models. ROS can occur upstream of DNA-damage signaling and apoptosis. MSeA can also act antioxidatively in some non-cancer or hormone-dependent contexts, so ROS direction is not universal.
2 Apoptosis and caspase signaling Apoptosis ↑; caspase-3/7/9 ↑; PARP cleavage ↑ Apoptosis ↔/lower (model-dependent) R/G Programmed cell death Strongly reproduced across prostate, breast, colon, glioma and other cancer systems. Execution pathway varies by cell type.
3 Protein thiol oxidation and PKC PKC activity ↓ ↔/↓ (context-dependent) P/R Redox inhibition of proliferative signaling MSeA oxidizes susceptible vicinal cysteine thiols in PKC catalytic domains. Ca²⁺-dependent PKC isoenzymes are particularly susceptible, but this does not establish Ca²⁺ signaling itself as a primary MSeA mechanism.
4 Endoplasmic reticulum stress PERK ↑; eIF2α phosphorylation ↑; GRP78 ↑; CHOP ↑; ER-stress apoptosis ↑ Uncertain R/G Proteotoxic stress and apoptosis Lower exposure activates adaptive ER-stress responses; greater stress shifts signaling toward CHOP/caspase-associated death.
5 Mitochondrial dysfunction Mitochondrial depolarization ↑; cytochrome-c release ↑; permeability transition ↑ (model-dependent) Lower effect reported in selected models R/G Intrinsic apoptotic amplification Mitochondrial involvement is closely linked to cellular redox state and AKT survival signaling. AIF-associated death has also been reported in selenium-compound models.
6 AKT survival signaling AKT phosphorylation ↓ or ↑ (context-dependent) ↔ (model-dependent) R/G Reduced survival signaling AKT commonly determines MSeA sensitivity, but direction is not uniform. Hypoxic prostate models can show AKT activation despite continued growth inhibition, so AKT↓ should not be treated as universal.
7 Androgen receptor signaling AR ↓; PSA ↓ Not established G Suppression of prostate-cancer growth signaling Repeatedly demonstrated across several AR-positive prostate cancer models and appears mechanistically distinct from selenite-mediated AR suppression.
8 β-Catenin signaling Total β-catenin ↓; nuclear β-catenin ↓ Not established G Reduced proliferation and drug resistance Suppression is dose- and time-dependent and can enhance cytotoxicity of multiple chemotherapeutic drugs.
9 HIF-1α and hypoxia signaling HIF-1α ↓; REDD1 ↑ Not established G Growth inhibition under hypoxia Relevant particularly in invasive prostate cancer. REDD1 induction can occur despite AKT activation and altered mTOR signaling.
10 Angiogenesis signaling VEGF ↓; Ang-2 ↓; neuropilin-1 ↓; microvascular density ↓ Vascular normalization ↑ (model-dependent) G Antiangiogenic activity Supported by breast- and prostate-tumor animal models as well as tumor-cell studies.
11 STAT3 and inflammatory survival signaling STAT3 ↓; NF-κB ↓ (model-dependent) Uncertain G Reduced survival and inflammatory signaling Mechanistically relevant but less consistently demonstrated than redox stress, apoptosis and ER stress.
12 Cell cycle Cell-cycle progression ↓; G1 or G2/M arrest ↑ (model-dependent) Lower effect in selected non-transformed cells G Antiproliferative effect Cell-cycle phenotype depends strongly on tumor lineage, concentration and exposure duration.
13 Chemosensitization Paclitaxel response ↑; etoposide response ↑; docetaxel response ↑ Limited data G Enhanced treatment efficacy Synergistic or strongly enhanced antitumor effects have been reported in cell and xenograft models. Clinical validation is absent.
14 Radiosensitization Radiation sensitivity ↑; lipid peroxidation ↑ Radiation toxicity ↔ at comparable MSeA exposure in selected fibroblast models R/G Selective radiation sensitization Demonstrated preclinically in head-and-neck cancer cells and linked to enhanced lipid peroxidation.
15 Thioredoxin reductase system TrxR interaction/modulation ↔/↑; high TrxR can confer resistance Selenoprotein activity ↑ (model-dependent) R/G Redox buffering and resistance determinant MSeA is a TrxR substrate rather than a simple irreversible TrxR inhibitor. TrxR can reverse MSeA-induced thiol oxidation, and increased TrxR may reduce sensitivity. Database coding as uniformly TrxR↓ would therefore be misleading.
16 Clinical Translation Constraint Effective concentrations commonly low µM in vitro Selenium toxicity limits unrestricted systemic dosing G Exposure and safety limitation No established therapeutic human MSeA exposure, dose, PK profile or anticancer efficacy. Rodent oral efficacy cannot be directly converted to a human treatment dose.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
Scientific Papers found: Click to Expand⟱
161- CUR,  MeSA,    Enhanced apoptotic effects by the combination of curcumin and methylseleninic acid: potential role of Mcl-1 and FAK
- in-vitro, BC, MDA-MB-231 - in-vitro, Pca, DU145
Mcl-1↑, Mcl-1↓, MPT↑, AIF↑, chemoPv↑, Apoptosis↑, ROS↑, FAK↓, STAT3↓, NF-kB↓,
8752- MeSA,  Rad,    Methylseleninic Acid Induces Lipid Peroxidation and Radiation Sensitivity in Head and Neck Cancer Cells
- in-vitro, HNSCC, CAL27 - in-vitro, SCC, SCC25
selectivity↑, RadioS↑, GSH↓, lipid-P↑, OCR↑,
8764- MeSA,    Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition
- in-vitro, Lung, A549
FOXO3↑, DNAdam↑, ROS↓, TumCCA↑, Apoptosis↑, ChemoSen↑, Glycolysis↓, TCA↓, Synergy↑,
8763- MeSA,    Methylseleninic Acid Provided at Nutritional Selenium Levels Inhibits Angiogenesis by Down-regulating Integrin β3 Signaling
- vitro+vivo, Nor, HUVECs
eff↑, angioG↓, ITGB3↓, p‑Akt↓, p‑IκB↓, p‑NF-kB↓,
8762- MeSA,    Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels
- in-vitro, Ovarian, A2780S
selectivity↑, NK cell↑, T-Cell↑, PD-L1↓, Hif1a↓, VEGF↓, ROS↑, *NRF2↑,
8761- MeSA,    Methylseleninic Acid Suppresses Breast Cancer Growth via the JAK2/STAT3 Pathway
- in-vitro, BC, 4T1
TumCI↓, Apoptosis↑, Casp3↑, PARP1↑, BAX↑, JAK2↓, STAT3↓,
8760- MeSA,  Cisplatin,    Methylseleninic acid overcomes programmed death-ligand 1-mediated resistance of prostate cancer and lung cancer
- vitro+vivo, Lung, NA - in-vitro, Pca, NA
PD-L1↓, ChemoSen↑, T-Cell↑,
8759- MeSA,    Methylseleninic acid induces apoptosis of human bladder cancer cells through the ROS-mediated mitochondrial pathway
- in-vitro, Bladder, J82 - in-vitro, CRC, T24/HTB-9
tumCV↓, TumCCA↑, Apoptosis↑, ROS↑, MMP↓, eff↓, BAX↑, Bcl-2↓, Cyt‑c↑, Casp9↑, Casp3↑,
8758- MeSA,    Targeting transforming growth factor-β1 by methylseleninic acid/seleno-L-methionine in clear cell renal cell carcinoma: Mechanisms and therapeutic potential
- vitro+vivo, RCC, 786-O - in-vitro, Kidney, Caki-1
TGF-β1↓, PD-L1↓, VEGF↓, TumCG↓,
8757- MeSA,    Methylseleninic acid (MSA) inhibits 17β-estradiol-induced cell growth in breast cancer T47D cells via enhancement of the antioxidative thioredoxin/ thioredoxin reductase system
- in-vitro, BC, T47D
ER-α36↓, TumCCA↑, Synergy↑, Trx↑, TrxR↑, ROS↓, other↝,
8756- MeSA,    THE MAIN CYTOTOXIC EFFECTS OF METHYLSELENINIC ACID ON VARIOUS CANCER CELLS
- Review, Var, NA
ROS↑, GSH↓, RadioS↑, angioG↓, p‑Akt↓, IκB↓, NF-kB↓, ITGB3↓, p‑FOXO3↓, BAX↑, Cyt‑c↑, proCasp3↑, PARP↑, Glycolysis↓, TCA↓, NRF2↑, DNMT1↓, Hif1a↓, ER Stress↑, ChemoSen↑,
8755- MeSA,    The Inhibitory Efficacy of Methylseleninic Acid Against Colon Cancer Xenografts in C57BL/6 Mice
- in-vivo, CRC, NA
TumCG↓, Dose↝, GPx↑, TNF-α↓, IL6↓,
8754- MeSA,    Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity
- in-vitro, CRC, RKO
Synergy↑, ER Stress↑, UPR↑,
8753- MeSA,    Methylseleninic acid inhibits human glioma growth in vitro and in vivo by triggering ROS-dependent oxidative damage and apoptosis
- vitro+vivo, GBM, U251 - in-vitro, GBM, U87MG
Apoptosis↑, Casp7↑, Casp9↑, Casp3↑, ROS↑, TumCG↓,
8751- MeSA,  PacT,    Methylseleninic acid enhances paclitaxel efficacy for the treatment of triple-negative breast cancer
- vitro+vivo, BC, MDA-MB-231
ChemoSen↑, Casp↑, Apoptosis↑, TumCCA↑, TumCP↓, TumCG↓,
8750- MeSA,    Methylseleninic acid restricts tumor growth in nude mice model of metastatic breast cancer probably via inhibiting angiopoietin-2
- vitro+vivo, BC, MDA-MB-231
ANGPT2↓, VEGF↓, TumVol↓, TumW↓,
8749- MeSA,  etoposide,    Methylseleninic acid enhances the effect of etoposide to inhibit prostate cancer growth in vivo
- in-vivo, Pca, NA
TumCG↓, Apoptosis↑, p‑ERK↓, p‑Akt↓, FABP5/E-FABP↓, angioG↓, VEGF↓, ChemoSen↑,
8748- MeSA,    Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia
- in-vitro, Pca, LNCaP - in-vitro, Pca, PC3
Hif1a↓, DDIT4?, p‑Akt↑, P70S6K↑, TumCG↓,
8747- MeSA,    Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers
- in-vitro, CRC, HT-29 - in-vitro, Laryn, FaDu - in-vitro, Pca, PC3 - in-vitro, CRC, HCT116
β-catenin/ZEB1↓, ChemoSen↑,
8746- MeSA,    Inhibition of androgen receptor signaling by selenite and methylseleninic acid in prostate cancer cells: two distinct mechanisms of action
- in-vitro, Nor, LAPC-4 - in-vitro, Pca, LNCaP
AR↓, GSH↝, PSA↓,
8745- MeSA,    Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers
- in-vitro, Pca, LNCaP
AR↓, PSA↓, AntiCan↑, DHCR24↓,
8744- MeSA,    Locally generated methylseleninic acid induces specific inactivation of protein kinase C isoenzymes: relevance to selenium-induced apoptosis in prostate cancer cells
- in-vitro, Pca, DU145
PKCδ↓, TumCG↓, Apoptosis↑,
8743- MeSA,    PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
Apoptosis↑, eff↝, p‑Akt↓, p‑ERK↑,
8742- MeSA,    Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells
- in-vitro, Pca, DU145
TumCCA↑, DNAdam↑, Casp↑, cl‑PARP↑, p27/CDKN1B↑, P21↑, Apoptosis↑, Akt↓, ERK↓,
8741- MeSA,    In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention
- vitro+vivo, Var, NA
Apoptosis↑, eff↑, eff↝, chemoPv↑,

Showing Research Papers: 1 to 25 of 25

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 25

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

GPx↑, 1,   GSH↓, 2,   GSH↝, 1,   lipid-P↑, 1,   NRF2↑, 1,   ROS↓, 2,   ROS↑, 5,   Trx↑, 1,   TrxR↑, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

OCR↑, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

DHCR24↓, 1,   FABP5/E-FABP↓, 1,   Glycolysis↓, 2,   TCA↓, 2,  

Cell Death(tgid=5) ⓘ

AIF↑, 1,   Apoptosis↑, 11,   BAX↑, 3,   Bcl-2↓, 1,   Casp↑, 2,   Casp3↑, 3,   proCasp3↑, 1,   Casp7↑, 1,   Casp9↑, 2,   Cyt‑c↑, 2,   Mcl-1↓, 1,   Mcl-1↑, 1,  

Kinase & Signal Transduction(tgid=6) ⓘ

Akt↓, 1,   p‑Akt↓, 4,   p‑Akt↑, 1,   DDIT4?, 1,   ERK↓, 1,   p‑ERK↓, 1,   p‑ERK↑, 1,   IκB↓, 1,   p‑IκB↓, 1,   JAK2↓, 1,   P70S6K↑, 1,   PKCδ↓, 1,   STAT3↓, 2,  

Transcription & Epigenetics(tgid=7) ⓘ

DNMT1↓, 1,   FOXO3↑, 1,   p‑FOXO3↓, 1,   other↝, 1,   tumCV↓, 1,  

Protein Folding & ER Stress(tgid=8) ⓘ

ER Stress↑, 2,   UPR↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 2,   PARP↑, 1,   cl‑PARP↑, 1,   PARP1↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

P21↑, 1,   p27/CDKN1B↑, 1,   TumCCA↑, 5,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

TumCG↓, 7,   TumCP↓, 1,  

Migration(tgid=13) ⓘ

ANGPT2↓, 1,   FAK↓, 1,   ITGB3↓, 2,   TGF-β1↓, 1,   TumCI↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 3,   Hif1a↓, 3,   VEGF↓, 4,  

Barriers & Transport(tgid=15) ⓘ

MMP↓, 1,   MPT↑, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

IL6↓, 1,   NF-kB↓, 2,   p‑NF-kB↓, 1,   NK cell↑, 1,   PD-L1↓, 3,   PSA↓, 2,   T-Cell↑, 2,   TNF-α↓, 1,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 2,   ER-α36↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 6,   Dose↝, 1,   eff↓, 1,   eff↑, 2,   eff↝, 2,   RadioS↑, 2,   selectivity↑, 2,   Synergy↑, 3,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 2,   IL6↓, 1,   PD-L1↓, 3,   PSA↓, 2,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 1,   chemoPv↑, 2,   TumVol↓, 1,   TumW↓, 1,  
Total Targets: 92

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

NRF2↑, 1,  
Total Targets: 1

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

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