1α,25-Dihydroxyvitamin D3 potentiates cisplatin antitumor activity by p73 induction in a squamous cell carcinoma model
Open Access
- 1 September 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 7 (9), 3047-3055
- https://doi.org/10.1158/1535-7163.mct-08-0243
Abstract
1α,25-Dihydroxyvitamin D3 (1,25D3) exhibits antitumor activity in a variety of cancers including squamous cell carcinoma (SCC). Intrinsic resistance of SCC cells to cisplatin was observed and led to the investigation into whether 1,25D3 sensitizes SCC cells to cisplatin. Pretreatment with 1,25D3 followed by cisplatin enhanced growth inhibition in SCC cells compared with 1,25D3 alone as assessed by cytotoxicity and in vitro clonogenic assays. In addition, 1,25D3 sensitized SCC cells to cisplatin-mediated apoptosis. Treatment of tumor-bearing C3H mice with 1,25D3 before cisplatin reduced clonogenic survival using in vivo excision clonogenic assay. These results were not observed in a 1,25D3-resistant SCC variant, indicating the critical role of 1,25D3 in sensitizing SCC cells to cisplatin. Further, a marked decrease in fractional tumor volume was observed when SCC tumor-bearing mice were treated with 1,25D3 before cisplatin compared with either agent administered alone. Cisplatin has been shown to modulate p73 protein level in certain cancer cells. Our data showed that p73 level was not affected by cisplatin but increased by 1,25D3 in SCC cells. Knocking down p73 by small interfering RNA protected SCC cells against 1,25D3 and cisplatin-mediated clonogenic cell kill and apoptosis. Increasing p73 protein level by knocking down UFD2a, which mediates p73 degradation, promoted 1,25D3 and cisplatin-mediated clonogenic cell kill. These results suggest that 1,25D3 potentiates cisplatin antitumor activity in vitro and in vivo in a SCC model system possibly through p73 induction and apoptosis. The combination treatment may provide a more effective therapeutic regimen in cancer treatment. [Mol Cancer Ther 2008;7(9):3047–55]Keywords
This publication has 48 references indexed in Scilit:
- Vitamin D signalling pathways in cancer: potential for anticancer therapeuticsNature Reviews Cancer, 2007
- The resurgence of platinum-based cancer chemotherapyNature Reviews Cancer, 2007
- Standard, and novel cytotoxic and molecular-targeted, therapies for HNSCC: an evidence-based reviewCurrent Opinion in Oncology, 2007
- CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53Blood, 2006
- Ubiquitin and Ubiquitin-Like Modifications of the p53 FamilyNeoplasia, 2006
- The role of p53 protein family in gastrointestinal malignanciesCell Death & Differentiation, 2006
- p73-Dependent Apoptosis through Death Receptor: Impairment by Human Cytomegalovirus InfectionCancer Research, 2005
- Cellular processing of platinum anticancer drugsNature Reviews Drug Discovery, 2005
- Cisplatin: mode of cytotoxic action and molecular basis of resistanceOncogene, 2003
- Vitamin D3-induced Apoptosis of Murine Squamous Cell Carcinoma CellsJournal of Biological Chemistry, 2001