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World J Stem Cells. Aug 26, 2026; 18(8): 121991
Published online Aug 26, 2026. doi: 10.4252/wjsc.121991
Cellular hypoxia reprograms drug response and reveals curcumin-driven cancer stem-cell-associated marker enrichment in oral squamous cell carcinoma
Hazar S Alharbi, Ishrat Rahman, Manal A AlSheddi, Hanan Henidi, Manal Mubarak Alkahtani, Zaha Al Makhlafi, Sahar ElRefai, Shams A Altwaim, Hourya Sanat Alnofaie, Hend M Salem, Maha Galal Omar, Alia Alturki, Hiba Talic, Ghada Aladhyani, Fotoon Alotaibi, Hadeel Basuhail, Rasil Alotaibi, Nada Alturki, Aljawhara Alharbi, Rafa Alsultan, Sara Khalid Albassam
Hazar S Alharbi, Ishrat Rahman, Manal A AlSheddi, Sahar ElRefai, Shams A Altwaim, Hourya Sanat Alnofaie, Hend M Salem, Maha Galal Omar, Alia Alturki, Sara Khalid Albassam, Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
Hanan Henidi, Manal Mubarak Alkahtani, Zaha Al Makhlafi, Department of Research, Natural and Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
Hiba Talic, Ghada Aladhyani, Fotoon Alotaibi, Hadeel Basuhail, Rasil Alotaibi, Nada Alturki, Aljawhara Alharbi, Rafa Alsultan, College of Dentistry, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
Author contributions: Alharbi HS, Rahman I, and AlSheddi MA conceptualized the research; Rahman I, AlSheddi MA, Henidi H, Alkahtani MM, and Al Makhlafi Z worked on the methodology; Henidi H, Alkahtani MM, Al Makhlafi Z, Talic H, Aladhyani G, Alotaibi F, Basuhail H, Alotaibi R, Alturki N, Alharbi A, and Alsultan R performed the experimental investigations; Rahman I, AlSheddi MA, Henidi H, and Alnofaie HS performed the data analysis; Rahman I, Talic H, Aladhyani G, Alotaibi F, Basuhail H, Alotaibi R, Alturki N, Alharbi A, Alsultan R, and Albassam SK contributed to writing the first draft of the manuscript; Rahman I, AlSheddi MA, ElRefai S, Altwaim SA, Alnofaie HS, Salem HM, Omar MG, Alturki A, and Albassam SK supervised the project and completed the writing and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.
AI contribution statement: ChatGPT, an AI-assisted language tool developed by OpenAI, was used only to support language refinement, clarity, and organization during manuscript preparation. Grammarly was used to improve language and grammar. No other AI tools were used in preparing this manuscript. The authors reviewed, edited, and approved all AI-assisted text and took full responsibility for the accuracy, integrity, originality, and scientific validity of the submitted work. AI tools were not used to generate original data or draw scientific conclusions, nor were they used to generate any portion of the main text of the responses to the reviewers’ comments.
Institutional review board statement: Expedited approval was given to conduct this research by the Institutional Review Board at King Abdullah bin Abdulaziz University Hospital (IRB: P23-0050).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets generated and/or analysed during the current study are available from the corresponding author upon reasonable request at
skalbassam@pnu.edu.sa.
Corresponding author: Sara Khalid Albassam, Assistant Professor, Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, Airport Road, Riyadh 11671, Saudi Arabia.
skalbassam@pnu.edu.sa
Received: April 7, 2026
Revised: May 30, 2026
Accepted: July 16, 2026
Published online: August 26, 2026
Processing time: 135 Days and 21.5 Hours
BACKGROUND
Oral squamous cell carcinoma is a deadly cancer often detected late, contributing to high mortality and treatment failure. The efficacy of first-line chemotherapeutic agents is limited by resistance and a narrow therapeutic index. Naturally derived compounds, including curcumin, are increasingly being explored for their anti-inflammatory and anticancer potential.
AIM
To determine whether curcumin retains cytotoxicity under hypoxia compared with carboplatin and assess apoptosis, reactive oxygen species (ROS), and stemness markers.
METHODS
The OECM-1 model of late-stage cancer cultured under hypoxic conditions was validated by measuring hypoxia-induced factor 1 alpha levels using enzyme-linked immunosorbent assay. Drug cytotoxicity was measured using the MTT assay. Oxidative stress was assessed using a DCFDA cellular ROS assay; apoptosis was determined using Annexin V staining; and surface cancer stem cell (CSC) markers were detected using flow cytometry with antibodies against CD44, CD133, and CD147. Dose-response curves were analyzed using nonlinear regression, and drug interactions were assessed using exploratory CI, Bliss, and Highest Single Agent analyses.
RESULTS
Hypoxia-induced factor 1 alpha levels were six-fold higher under hypoxia than normoxia (P = 0.0032). Curcumin retained cytotoxic activity under hypoxia, whereas carboplatin potency and efficacy declined. Combining carboplatin with curcumin reduced curcumin potency under hypoxia and did not show synergy by exploratory CI, Bliss, or Highest Single Agent analyses. Carboplatin did not significantly alter ROS levels, whereas curcumin alone or in combination with carboplatin reduced ROS under normoxia and hypoxia (P = 0.039 to P < 0.0001). Treatments did not induce apoptosis under normoxia but increased apoptosis under hypoxia. Carboplatin did not alter the expression of CD44, CD133, or CD147 in either model, whereas curcumin and the combined treatment increased the expression of CSC-associated markers, particularly CD44+CD133+ under hypoxia (P < 0.0001).
CONCLUSION
Curcumin retained cytotoxic activity in a hypoxic, chemoresistant late-stage model where carboplatin activity declined, but increased CSC-associated marker expression, requiring functional validation.
Core Tip: Curcumin retained cytotoxic activity in oral squamous cell carcinoma under hypoxic, chemoresistant conditions where carboplatin activity declined. Its effects were associated with apoptosis induction and reduced reactive oxygen species, suggesting cytotoxicity that may not depend solely on increased oxidative stress. However, curcumin also increased cancer stem cell-associated marker expression, particularly under hypoxia. This marker enrichment may reflect selective survival, phenotypic adaptation, or stress-induced reprogramming, but functional validation is required. These findings highlight the importance of hypoxia in shaping drug response and treatment-associated cellular adaptation in oral squamous cell carcinoma.
