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Eurasian Journal of
Medicine and Oncology FN3K–Nrf2 axis inhibition in breast cancer

– MCF-7, T-47D, and BT-474 – as well as in the non- exhibits tumor-selective activity, potentially minimizing the
malignant Vero cell line. This analysis aimed to explore risk of off-target effects in non-cancerous cells.
the differential modulation of FN3K and Nrf2 following
treatment with oxaliplatin, lansoprazole, and capivasertib, 3.2.3.2. Nrf2 inhibition follows FN3K suppression selectively in
thereby evaluating both the selectivity and efficacy of these cancer cells
agents in targeting cancerous versus non-cancerous cells. In cancer cells, Nrf2 expression was significantly
As shown in Table 4, all three compounds significantly downregulated (↓90.1 – 98.5%) following treatment
suppressed FN3K and Nrf2 expression in the breast cancer with the tested compounds. In Vero cells, however, Nrf2
cell lines, with lansoprazole and oxaliplatin showing the expression level remained unchanged or was only mildly
most potent effects. Notably, the FN3K fold changes in suppressed (↓5 – 11%). This pattern further supports
cancer cells decreased by more than 99% across all three the selectivity of FN3K-targeting compounds for tumor
treatments, while expression in Vero cells remained largely suppression.
unaffected, highlighting their selective activity toward 3.2.3.3. Capivasertib demonstrates the highest FN3K selectivity
malignant cells. Similar trends were observed for Nrf2, among the tested compounds
with up to 98.5% downregulation in cancer lines and only Among the three compounds, capivasertib exhibited the
minimal suppression observed in the Vero cell line.
greatest selectivity. In breast cancer cells (MCF-7, T-47D,
This comparative analysis provides critical insights into BT-474), capivasertib strongly inhibited FN3K expression
the therapeutic potential of FN3K-targeted inhibition and (↓99.88 – 99.98%). In contrast, FN3K expression in Vero
its downstream impact on Nrf2-regulated oxidative stress cells remained unchanged, indicating no significant impact
pathways, which are often upregulated in cancer cells to on non-malignant cells. This suggests that capivasertib may
promote survival and resistance to therapy. serve as the most specific FN3K inhibitor among the three.

3.2.3.1. FN3K inhibition exhibits high selectivity for cancer cells 3.3. Statistical analysis
with minimal effects in normal cells
As shown in Table 4, oxaliplatin, lansoprazole, and 3.3.1. Differential expression of FN3K and Nrf2 in MCF-7 Cells
capivasertib all demonstrated strong FN3K downregulation qPCR analysis of FN3K and Nrf2 gene expression in
(↓99.6 – 99.99%) in breast cancer cell lines. In contrast, FN3K MCF-7 breast cancer cells treated with oxaliplatin,
expression in non-malignant Vero cells remained largely lansoprazole, capivasertib, amiloride, ritonavir, and 1-DMF
unaffected, with only a modest reduction of 9 – 12%. These demonstrated notable alterations in transcript levels.
findings indicate that FN3K inhibition by these compounds Statistical evaluation was performed using either Welch’s

Table 4. Comparative qPCR analysis of FN3K and Nrf2 downregulation in cancer (MCF-7, T-47D, BT-474) versus normal (Vero) cells
Treatment FN3K fold change FN3K fold FN3K fold change FN3K fold change Interpretation
(MCF-7) change (T-47D) (BT-474) (Vero)
Untreated (control) 1.00 1.01 1.02 1.04 Baseline expression in all cell lines.
Oxaliplatin 0.00002 (↓99.99%) 0.0039 (↓99.6%) 0.0029 (↓99.7%) 0.88 (↓12%) Selective FN3K inhibition in cancer cells,
minimal effect in Vero cells.
Lansoprazole 0.00097 (↓99.90%) 0.0001 (↓99.99%) 0.0002 (↓99.98%) 0.91 (↓9%) Highly selective FN3K inhibition in cancer
cells, minimal suppression in Vero cells.
Capivasertib 0.00017 (↓99.98%) 0.00026 (↓99.97%) 0.0012 (↓99.88%) 1.01 (No change) Strong FN3K suppression in cancer cells, no
effect in Vero cells.
Treatment Nrf2 fold change Nrf2 fold change Nrf2 fold change Nrf2 fold change Interpretation
(MCF-7) (T-47D) (BT-474) (Vero)
Untreated (Control) 1.02 1.06 1.05 1.00 Baseline expression in all cell lines.
Oxaliplatin 0.0318 (↓96.8%) 0.0283 (↓97.3%) 0.1041 (↓90.1%) 1.01 (No change) Selective Nrf2 inhibition in cancer cells, no
effect in Vero cells.
Lansoprazole 0.0152 (↓98.5%) 0.0289 (↓97.2%) 0.0595 (↓94.3%) 0.89 (↓11%) Strong Nrf2 inhibition in cancer cells, mild
effect in Vero cells.
Capivasertib 0.0629 (↓93.8%) 0.0563 (↓94.7%) 0.0673 (↓93.5%) 0.95 (↓5%) Significant Nrf2 suppression in cancer cells,
minimal effect in Vero cells.
Note: ↓indicates percent downregulation in gene expression relative to control (untreated) levels.
Abbreviation: FN3K: Fructosamine-3-kinase.
Volume 9 Issue 3 (2025) 210 doi: 10.36922/EJMO025150114