Glucose-Dependent Cytotoxic Responses in Triple-Negative Breast Cancer: Experimental and Transcriptomic Evidence of Metabolic Context and p38 MAPK-Associated Modulation
9 affiliations
- 1Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
- 2Research Department, Natural and Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
- 3College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
- 4College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
- 5Department of Pharmaceutical Sciences, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- 6King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia
- 7King Abdulaziz Medical City, National Guard Health Affairs (NGHA), Riyadh, Saudi Arabia
- 8Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
- 9Microbiology and Immunology Unit, Natural and Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
Abstract
Background: Triple-negative breast cancer exhibits substantial metabolic heterogeneity, which may influence therapeutic response. This study investigated whether thymoquinone, glabridin, and glycyrrhizic acid exhibit context-dependent cytotoxicity under glucose deprivation and hypoxia, and whether pharmacological inhibition of p38 MAPK modifies these responses.
Methods: MDA-MB-231 and MCF-7 cells were treated in 2D monolayer culture with thymoquinone, glabridin, glycyrrhizic acid, or doxorubicin under normoxic, glucose-deprived, and hypoxic conditions. Cell viability was assessed by MTT assay, and p38 involvement was explored using SB203580 co-treatment. Selectivity was assessed in MCF-10A cells. Thymoquinone silver-nanoparticles were also evaluated. Bulk TCGA-BRCA basal-like and receptor-defined TNBC cohorts and GSE118389 single-cell TNBC RNA-seq data were analyzed for glycolysis, hypoxia, p38 MAPK, epithelial–mesenchymal transition, stemness, and oxidative-stress signatures.
Results: In MDA-MB-231 cells, glabridin showed greater cytotoxicity under glucose-replete conditions, whereas glycyrrhizic acid became more cytotoxic during glucose deprivation. The effect of SB203580 varied according to metabolic context, supporting pharmacologically inferred rather than directly validated p38 involvement. Doxorubicin activity was reduced under hypoxia, whereas thymoquinone retained cytotoxic activity. Thymoquinone nanoparticles did not demonstrate clear therapeutic selectivity. Transcriptomic analyses identified a glycolysis–hypoxia relationship. After false-discovery-rate correction, higher p38-related transcriptional activity was associated with increased EMT scores in both bulk TNBC cohorts. Hallmark sensitivity analyses additionally showed higher glycolysis, hypoxia, and EMT scores in p38-high tumors. Single-cell analyses identified similar metabolic-stress and adaptive associations but were exploratory because cells were derived from only six tumors.
Conclusion: Metabolic context influenced cytotoxic responses in TNBC. These findings support further investigation of microenvironment-adapted therapies, while p38-related mechanisms require direct validation.
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BibTeX
@article{rahman2026glucosedependent,
title = {{Glucose-Dependent Cytotoxic Responses in Triple-Negative Breast Cancer: Experimental and Transcriptomic Evidence of Metabolic Context and p38 MAPK-Associated Modulation}},
author = {Ishrat Rahman and Hanan Henidi and Aisha Alshibli and Nouf Saleh Bin-Murdhi and Maram Saud Alqutaym and Manal Alsheddi and Sahar Alghamdi and Aljawharah F Bin Rayyis Snr and Reem Abdullah Alqahtani and Lubna khalid Aljaddua and Afrah E Mohammed},
journal = {Breast Cancer : Targets and Therapy},
year = {2026},
month = oct,
doi = {10.2147/bctt.s623153},
url = {https://doi.org/10.2147/bctt.s623153},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Glucose-Dependent Cytotoxic Responses in Triple-Negative Breast Cancer: Experimental and Transcriptomic Evidence of Metabolic Context and p38 MAPK-Associated Modulation
AU - Ishrat Rahman
AU - Hanan Henidi
AU - Aisha Alshibli
AU - Nouf Saleh Bin-Murdhi
AU - Maram Saud Alqutaym
AU - Manal Alsheddi
AU - Sahar Alghamdi
AU - Aljawharah F Bin Rayyis Snr
AU - Reem Abdullah Alqahtani
AU - Lubna khalid Aljaddua
AU - Afrah E Mohammed
PY - 2026
DA - 2026/10/22
JO - Breast Cancer : Targets and Therapy
DO - 10.2147/bctt.s623153
UR - https://doi.org/10.2147/bctt.s623153
AB - Background: Triple-negative breast cancer exhibits substantial metabolic heterogeneity, which may influence therapeutic response. This study investigated whether thymoquinone, glabridin, and glycyrrhizic acid exhibit context-dependent cytotoxicity under glucose deprivation and hypoxia, and whether pharmacological inhibition of p38 MAPK modifies these responses. Methods: MDA-MB-231 and MCF-7 cells were treated in 2D monolayer culture with thymoquinone, glabridin, glycyrrhizic acid, or doxorubicin under normoxic, glucose-deprived, and hypoxic conditions. Cell viability was assessed by MTT assay, and p38 involvement was explored using SB203580 co-treatment. Selectivity was assessed in MCF-10A cells. Thymoquinone silver-nanoparticles were also evaluated. Bulk TCGA-BRCA basal-like and receptor-defined TNBC cohorts and GSE118389 single-cell TNBC RNA-seq data were analyzed for glycolysis, hypoxia, p38 MAPK, epithelial–mesenchymal transition, stemness, and oxidative-stress signatures. Results: In MDA-MB-231 cells, glabridin showed greater cytotoxicity under glucose-replete conditions, whereas glycyrrhizic acid became more cytotoxic during glucose deprivation. The effect of SB203580 varied according to metabolic context, supporting pharmacologically inferred rather than directly validated p38 involvement. Doxorubicin activity was reduced under hypoxia, whereas thymoquinone retained cytotoxic activity. Thymoquinone nanoparticles did not demonstrate clear therapeutic selectivity. Transcriptomic analyses identified a glycolysis–hypoxia relationship. After false-discovery-rate correction, higher p38-related transcriptional activity was associated with increased EMT scores in both bulk TNBC cohorts. Hallmark sensitivity analyses additionally showed higher glycolysis, hypoxia, and EMT scores in p38-high tumors. Single-cell analyses identified similar metabolic-stress and adaptive associations but were exploratory because cells were derived from only six tumors. Conclusion: Metabolic context influenced cytotoxic responses in TNBC. These findings support further investigation of microenvironment-adapted therapies, while p38-related mechanisms require direct validation.
SN - 1179-1314
ER -