Exploring Vitamin D Metabolism in Gynaecological Malignancies: Redox-Dependent and Redox-Independent Anticancer Mechanisms From Preclinical Models to Clinical Evidence.
4 affiliations
- 1Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng, South Africa.
- 2Vitamin D Cancer Group, Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
- 3Department of Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng, South Africa.
- 4Division of Chemical Pathology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
Abstract
Gynaecological malignancies account for over 1.4 million new diagnoses, with outcomes constrained by late-stage presentation and chemoresistance. Dysregulated redox homeostasis is a hallmark of tumourigenesis. Tumour cells maintain elevated basal reactive oxygen species (ROS), which support proliferative signalling but may also increase susceptibility to further oxidative stress. Vitamin D, acting through the vitamin D receptor (VDR), has antiproliferative and pro-apoptotic effects across cancer models, but its ability to amplify ROS beyond an apoptotic threshold in gynaecological malignancies remains unresolved. We conducted a narrative literature search of PubMed/MEDLINE, ClinicalTrials.gov and the Surveillance, Epidemiology and End Results databases, using terms related to vitamin D and its metabolites, ROS/oxidative stress, apoptosis and gynaecological malignancies. Preclinical evidence indicates that calcitriol and related compounds can induce ROS-mediated mitochondrial apoptosis, modulate autophagy and arrest the cell cycle. In ovarian cancer, non-HGSOC cell data suggest that mutant TP53 may alter calcitriol responses, requiring validation in high-grade serous ovarian carcinoma models. In cervical cancer, calcitriol radiosensitises human papillomavirus-positive cell lines through autophagy suppression, whilst an in vivo calcitriol-cisplatin study reported improved survival. In endometrial cancer, thioredoxin-interacting protein induction is a candidate mechanism for selective ROS-mediated apoptosis, although this remains context-dependent. Clinical evidence is heterogeneous: higher 25-hydroxyvitamin D status has shown modest inverse associations with ovarian cancer mortality; small trials report regression or reduced recurrence of cervical intraepithelial neoplasia; no randomised controlled trial evidence supports efficacy in invasive cervical cancer; and associations with endometrial cancer incidence are largely null. Current evidence does not support vitamin D supplementation as an oncology-specific intervention. Future research should prioritise biomarker-stratified trials incorporating VDR genotype, CYP24A1 profiling, pre-specified 25(OH)D targets and pharmacokinetically informed dosing.
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BibTeX
@article{chan2026exploring,
title = {{Exploring Vitamin D Metabolism in Gynaecological Malignancies: Redox-Dependent and Redox-Independent Anticancer Mechanisms From Preclinical Models to Clinical Evidence.}},
author = {Hoi Ching Cherry Chan and Sachin Bhoora and Esther Zhou and Sumari Marais and Rivak Punchoo},
journal = {Cancer medicine},
year = {2026},
month = oct,
doi = {10.1002/cam4.72292},
url = {https://europepmc.org/article/MED/42910745},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Exploring Vitamin D Metabolism in Gynaecological Malignancies: Redox-Dependent and Redox-Independent Anticancer Mechanisms From Preclinical Models to Clinical Evidence.
AU - Hoi Ching Cherry Chan
AU - Sachin Bhoora
AU - Esther Zhou
AU - Sumari Marais
AU - Rivak Punchoo
PY - 2026
DA - 2026/10/01
JO - Cancer medicine
DO - 10.1002/cam4.72292
UR - https://europepmc.org/article/MED/42910745
AB - Gynaecological malignancies account for over 1.4 million new diagnoses, with outcomes constrained by late-stage presentation and chemoresistance. Dysregulated redox homeostasis is a hallmark of tumourigenesis. Tumour cells maintain elevated basal reactive oxygen species (ROS), which support proliferative signalling but may also increase susceptibility to further oxidative stress. Vitamin D, acting through the vitamin D receptor (VDR), has antiproliferative and pro-apoptotic effects across cancer models, but its ability to amplify ROS beyond an apoptotic threshold in gynaecological malignancies remains unresolved. We conducted a narrative literature search of PubMed/MEDLINE, ClinicalTrials.gov and the Surveillance, Epidemiology and End Results databases, using terms related to vitamin D and its metabolites, ROS/oxidative stress, apoptosis and gynaecological malignancies. Preclinical evidence indicates that calcitriol and related compounds can induce ROS-mediated mitochondrial apoptosis, modulate autophagy and arrest the cell cycle. In ovarian cancer, non-HGSOC cell data suggest that mutant TP53 may alter calcitriol responses, requiring validation in high-grade serous ovarian carcinoma models. In cervical cancer, calcitriol radiosensitises human papillomavirus-positive cell lines through autophagy suppression, whilst an in vivo calcitriol-cisplatin study reported improved survival. In endometrial cancer, thioredoxin-interacting protein induction is a candidate mechanism for selective ROS-mediated apoptosis, although this remains context-dependent. Clinical evidence is heterogeneous: higher 25-hydroxyvitamin D status has shown modest inverse associations with ovarian cancer mortality; small trials report regression or reduced recurrence of cervical intraepithelial neoplasia; no randomised controlled trial evidence supports efficacy in invasive cervical cancer; and associations with endometrial cancer incidence are largely null. Current evidence does not support vitamin D supplementation as an oncology-specific intervention. Future research should prioritise biomarker-stratified trials incorporating VDR genotype, CYP24A1 profiling, pre-specified 25(OH)D targets and pharmacokinetically informed dosing.
SN - 2045-7634
ER -