salinomycin / mTOR Cancer Research Results

Sal, salinomycin: Click to Expand ⟱
Features:
Salinomycin is a polyether ionophore antibiotic that is produced by the bacterium Streptomyces albus. It was first isolated in 1979 and has been found to have a range of biological activities, including antibacterial, antifungal, and anticancer properties.
It has been shown to induce apoptosis (programmed cell death) in a range of cancer cell lines, including breast, lung, and colon cancer cells. Salinomycin has also been found to inhibit the growth of cancer stem cells.
Salinomycin, a widely used antibiotic in poultry farming
Actions:
-Strong activity against cancer stem cells
-Disrupts mitochondrial ion gradients → ROS
-Non-thiol, non-NRF2 dominant

Key pathways
-Mitochondrial K⁺ dysregulation
-ROS-mediated apoptosis
-Wnt/β-catenin inhibition

Chemo relevance
-Generally compatible or synergistic
-Not a redox buffer

Rank Pathway / Target Axis Direction Primary Effect Notes / Cancer Relevance Ref
1 K+ ionophore activity / ionic homeostasis ↑ K+ transport (ionophore) / ↓ intracellular K+ homeostasis Electrochemical disruption Salinomycin is directly described as a potassium ionophore in mechanistic studies of its anticancer effects (ref)
2 Cancer stem cell (CSC) fraction / stemness programs ↓ CSC proportion / tumor-initiating capacity Selective CSC depletion Landmark study showing salinomycin strongly reduces CSC proportion (e.g., >100-fold vs paclitaxel in their assay context) and inhibits tumor growth in vivo (ref)
3 Wnt/β-catenin signaling ↓ Loss of self-renewal signaling Primary mechanistic paper identifying salinomycin as an inhibitor of the Wnt signaling cascade (ref)
4 Wnt co-receptor LRP6 (Wnt pathway control point) ↓ LRP6 / ↓ Wnt signaling Wnt pathway suppression Shows salinomycin suppresses LRP6 expression at concentrations relevant to growth inhibition, linking activity to Wnt/β-catenin suppression (ref)
5 Autophagic flux + lysosomal proteolysis ↓ autophagic flux (blocked) / ↓ lysosomal proteolytic activity Abortive autophagy / stress accumulation Demonstrates salinomycin blocks autophagic flux and lysosomal proteolytic activity in breast cancer CSC and non-CSC populations (ref)
6 ER stress / UPR (ATF4 → CHOP/DDIT3) ↑ ER stress / ↑ CHOP axis Proteotoxic stress signaling Shows salinomycin stimulates ER stress and mediates autophagy through the ATF4–CHOP–TRIB3 axis (ref)
7 AKT–mTOR survival signaling (via TRIB3) ↓ AKT / ↓ mTOR signaling Reduced survival + altered autophagy control Same mechanistic work links ER stress activation to TRIB3-mediated inhibition of AKT1–mTOR signaling after salinomycin exposure (ref)
8 ROS generation and ROS-linked lysosomal dysfunction ↑ ROS Oxidative stress amplification Demonstrates salinomycin-induced ROS and connects ROS to lysosomal membrane permeability and impaired autophagy flux (ref)
9 Mitochondrial apoptosis (caspase cascade) ↑ Caspase-9/3 activation Programmed cell death Shows salinomycin triggers caspase-dependent apoptosis involving caspases (including 9 and 3) in a salinomycin toxicity/mechanism study (demonstrates directionality for caspase activation) (ref)
10 EMT phenotype ↑ E-cadherin / ↓ vimentin (EMT suppressed) Reduced migration/invasion Reports salinomycin increases epithelial markers and decreases mesenchymal markers in a dose-dependent manner, with reduced migration/invasion (ref)
11 ABC transporter–mediated multidrug resistance ↓ functional MDR phenotype Overcomes drug resistance Directly reports salinomycin overcomes ABC transporter–mediated multidrug/apoptosis resistance in leukemia stem cell–like cells (ref)
12 Ferroptosis susceptibility (GPX4 axis) in CSC context ↑ ferroptosis (context-dependent) Non-apoptotic oxidative death modality Reports salinomycin induces ferroptosis in a CSC context via a pathway converging on GPX4/GPX activity regulation (directionality: ferroptosis induction by salinomycin in that model) (ref)


mTOR, mammalian target of rapamycin: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
mTOR (mechanistic target of rapamycin) is a central regulator of cell growth, proliferation, metabolism, and survival. It is a serine/threonine kinase that integrates signals from nutrients, growth factors, and cellular energy status.
mTOR promotes protein synthesis and cell growth by activating downstream targets such as S6 kinase and 4E-BP1. In cancer, this pathway can become hyperactivated, leading to uncontrolled cell proliferation.

mTor Inhibitors:
-rapamycin (Sirolimus): classic natural product mTOR inhibitor
-Curcumin
-Resveratrol
-Epigallocatechin Gallate (EGCG)
-Honokiol
Scientific Papers found: Click to Expand⟱
4901- DCA,  Sal,    Dichloroacetate and Salinomycin as Therapeutic Agents in Cancer
- Review, NSCLC, NA
Glycolysis↓, DCA redirects mitochondrial metabolism away from glycolysis to OXPHOS by the inhibition of PDKs
OXPHOS↑,
PDKs↓,
ROS↑, DCA increases reactive oxygen species (ROS), which induce downstream changes in mitochondrial function, causing the selective apoptosis of cancer cells.
Apoptosis↑,
GlucoseCon↓, treatment with DCA decreased glucose consumption and lactate production in vitro in a manner that was statistically significant compared to the controls
lactateProd↓,
RadioS↑, it enhanced the sensitivity of A549 and H1299 cells to X-ray-induced cell killing
TumAuto↑, DCA has been shown to induce autophagy instead of inhibiting it.
mTOR↓, The DCA-induced induction of autophagy was found to be mediated by the generation of ROS, the inhibition of the mammalian targets of rapamycin (mTOR),
LC3s↓, Lu and colleagues found that LC3 decreased while p62 levels increased, both of which are hallmarks of autophagy inhibition
p62↑,
TumCG↓, In vivo studies have demonstrated that DCA inhibits the growth of A549 and H1975 tumor xenografts and enhances the survival of tumor-bearing nude mice
OS↑,
toxicity↝, the most clinically limiting side effect of DCA is peripheral neuropathy
ChemoSen↑, DCA exerts synergistic potential with the most widely used chemotherapy agent, paclitaxel, on NSCLC cells.
Synergy↑, DCA has also been shown to have anticancer synergies with various non-traditional agents, the most prominent of which is metformin.
Synergy↑, Another compound that DCA has been shown to have a strong synergism with is ivermectin.
Ferritin↓, SAL and its derivatives prevent the movement of iron from the lumen to the cytosol, triggering an iron-depletion reaction that is characterized by the rapid degradation of ferritin
CSCs↓, SAL has been shown to selectively target CSCs in vitro and in vivo, but its mode of action is not fully understood.
EMT↓, SAL has also been shown to suppress the epithelial–mesenchymal transition (EMT) as well as transforming growth factors (TGFs). EMT is a process that is pivotal to metastasis.
ROS↑, SAL triggers apoptosis by elevating intracellular ROS levels, leading to the translocation of Bax protein to the mitochondria, cytochrome c (Cytc) release, and the activation of caspase-3
Cyt‑c↑,
Casp3↑,
ER Stress↑, SAL was observed to upregulate ER stress-related proteins in a time-/dose-dependent manner
selectivity↑, SAL induced cell death in multiple apoptosis-resistant cancer cell lines, but not in normal healthy human cells
Synergy↑, Skeberdytė and colleagues were among the first to recognize that DCA had synergistic potential with SAL.
TumCG↓, DCA and SAL were found to significantly suppress tumor growth in vivo in the mice.

4900- Sal,    Anticancer Mechanisms of Salinomycin in Breast Cancer and Its Clinical Applications
- Review, BC, NA
CSCs↓, Salinomycin, a monocarboxylic polyether antibiotic isolated from Streptomyces albus, can precisely kill cancer stem cells (CSCs), particularly BCSCs, by various mechanisms, including apoptosis, autophagy, and necrosis.
Apoptosis↑,
TumAuto↑,
necrosis↑,
TumCP↓, salinomycin can inhibit cell proliferation, invasion, and migration in BC and reverse the immune-inhibitory microenvironment to prevent tumor growth and metastasis.
TumCI↓,
TumCMig↓,
TumCG↓,
TumMeta↓,
eff↑, Salinomycin is over 100 times more effective against BCSCs than paclitaxel, the traditional chemotherapy drug for the treatment of BC
Bcl-2↓, downregulation of Bcl-2 expression, and decreases their migration capacity, which is accompanied by downregulation of c-Myc and Snail expression
cMyc↓,
Snail↓,
ALDH↓, salinomycin reduces aldehyde dehydrogenase activity and the expression of MYC, AR, and ERG; it induces oxidative stress and inhibits nuclear factor (NF)-κB activity
Myc↓,
AR↓,
ROS↑, Salinomycin also induces autophagy by increasing intracellular ROS level, which is accompanied by MAPK signaling pathway activation
NF-kB↓,
PTCH1↓, significantly reduces tumor growth, which is accompanied by decreased PTCH, SMO, Gli1, and Gli2 expression
Smo↓,
Gli1↓,
GLI2↓,
Wnt↓, Figure 2
mTOR↓,
GSK‐3β↓,
cycD1/CCND1↓,
survivin↓,
P21↑,
p27/CDKN1B↑,
CHOP/DDIT3↑,
Ca+2↑, cytosolic
DNAdam↑,
Hif1a↓,
VEGF↓,
angioG↓,
MMP↓, salinomycin can affect the cell membrane potential and reduce the level of ATP to induce mitophagy and mitoptosis.
ATP↓,
p‑P53↑, Salinomycin increases DNA breaks in BC cells as well as the expression of phosphorylated p53 and γH2AX in Hs578T cells.
γH2AX↑,
ChemoSen↑, Table 3 Synergistic anticancer co-action of salinomycin with other agents in BC.

4912- Sal,    Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells
- in-vitro, Lung, A549 - in-vitro, Lung, H460 - in-vitro, Lung, Calu-1 - in-vitro, Lung, H157
CSCs↓, Salinomycin is perhaps the first promising compound that was discovered through high throughput screening in cancer stem cells.
TumAuto↑, salinomycin induced autophagy in human non-small cell lung cancer (NSCLC) cells
ER Stress↑, salinomycin stimulated endoplasmic reticulum stress and mediated autophagy via the ATF4-DDIT3/CHOP-TRIB3-AKT1-MTOR axis.
TumCD↑, salinomycin effectively decreased the survival of the indicated cells in a dose-dependent manner
ATF4↑, Salinomycin induces autophagy via ER stress-dependent upregulation of ATF4 and DDIT3
CHOP/DDIT3↑,
AKT1↓, salinomycin via AKT1-MTOR inhibition in human NSCLC cells.
mTOR↓,


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(tgid=1) ⓘ

ROS↑, 3,  

Metal & Cofactor Biology(tgid=2) ⓘ

Ferritin↓, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

OXPHOS↑, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ATP↓, 1,   GlucoseCon↓, 1,   Glycolysis↓, 1,   GSK‐3β↓, 1,   lactateProd↓, 1,   PDKs↓, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 2,   Bcl-2↓, 1,   Casp3↑, 1,   Cyt‑c↑, 1,   necrosis↑, 1,   survivin↓, 1,   TumCD↑, 1,  

Kinase & Signal Transduction(tgid=6) ⓘ

AKT1↓, 1,   mTOR↓, 3,  

Transcription & Epigenetics(tgid=7) ⓘ

ATF4↑, 1,   cMyc↓, 1,   Myc↓, 1,  

Protein Folding & ER Stress(tgid=8) ⓘ

CHOP/DDIT3↑, 2,   ER Stress↑, 2,  

Autophagy & Lysosomes(tgid=9) ⓘ

LC3s↓, 1,   p62↑, 1,   TumAuto↑, 3,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 1,   p‑P53↑, 1,   γH2AX↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

cycD1/CCND1↓, 1,   P21↑, 1,   p27/CDKN1B↑, 1,  

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

ALDH↓, 1,   CSCs↓, 3,   Gli1↓, 1,   PTCH1↓, 1,   Smo↓, 1,   TumCG↓, 3,   TumCP↓, 1,   Wnt↓, 1,  

Migration(tgid=13) ⓘ

Ca+2↑, 1,   EMT↓, 1,   GLI2↓, 1,   Snail↓, 1,   TumCI↓, 1,   TumCMig↓, 1,   TumMeta↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 1,   Hif1a↓, 1,   VEGF↓, 1,  

Barriers & Transport(tgid=15) ⓘ

MMP↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

NF-kB↓, 1,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 2,   eff↑, 1,   RadioS↑, 1,   selectivity↑, 1,   Synergy↑, 3,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 1,   Ferritin↓, 1,   Myc↓, 1,  

Functional Outcomes(tgid=23) ⓘ

OS↑, 1,   toxicity↝, 1,  
Total Targets: 63

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: mTOR, mammalian target of rapamycin
3 salinomycin
1 Dichloroacetate
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#:203  Target#:209  State#:%  Dir#:1
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