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							| Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007



	

				
						
 
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																Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007
										

				


				
				
					
					
						
																					
				
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					Vol. 13 No. 3 (2023): March 2023
				
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									Review Articles
							
		



	
		  	 

		
	
		Combinations of vitamin A and D are synergistic in breast cancer cells and alter gene expression in the endoplasmic reticulum stress, unfolded protein and estrogen signaling canonical pathways
	


	
	
		

							
					Authors

						
							
								Pinal N. Kanabar
							
																																		
	
							
								Nina S. Los
							
																																		
	
							
								Temitope O. Lawal
							
																																		
	
							
								Shitalben M. Patel
							
																																		
	
							
								Nisikant A. Raut
							
																																		
	
							
								Mark Maienschein-Cline
							
																																		
	
							
								Zarema Arbieva
							
																																		
	
							
								Gail Mahady
							
																																		


				
			
																	
					
												DOI:
					

					
						
							https://doi.org/10.31989/ffhd.v13i3.1069
						
					
				
			

						
										
					Abstract

					Introduction: Numerous studies over the past 30 years have shown that bioactive compounds present in functional foods, including vitamins, minerals and phytochemicals reduce cancer risk. For example, vitamins A and D derivatives found in fruits, vegetables, and dairy products, reduce the growth of breast, bladder, head, neck, lung, prostate, and skin cancers. However, the effects of these combined vitamins have not been previously reported for breast cancer.
Aims: To investigate the activities of vitamin A (all-trans-retinoic acid; ATRA), as well as vitamins D2 and D3 in combination in the breast epithelial cancer cell lines T47D:A18, MCF-7, and SK-BR-3 and perform whole genome analysis in MCF-7 cells using RNA-seq.
Methods: Breast cancer cells were cultured in appropriate media and treated with ATRA, D2 or D3 alone in concentrations from 1-10 μg/ml, or in combination at 1, 5, and 10 μg/ml. The CellTiter-Glo® 2.0 assay, Caspase-Glo®3/7, Caspase®8, and ApoTox-Glo™ Triplex assays measured cell viability and apoptosis. The effect of treatment on autophagy in MCF-7 cells was measured with a CYTO-ID® Autophagy Detection Kit 2.0. The whole transcriptome analysis was assessed using mRNA-seq and qPCR.
Results: Separately, ATRA, D2, and D3 all reduced the viability of all breast cancer cell lines tested, with median inhibitory concentrations (IC50) between 2.1 to 31.7 μg/ml. However, when breast cancer cells were treated with combinations of ATRA+D2+D3, the IC50 was reduced indicating synergism. In MCF-7 cells, 5-flurouracil (5-FLU) had an IC50 of 1.37 µg/ml, while the vitamin A and D combination had an IC50 of 1.5 µg/ml, indicating the combination was ~90% as effective as 5-FLU. Treatment of MCF-7 cells with ATRA+D2+D3 enhanced caspase 3/7 activity, as well as the expression of Bax, BAD, PTEN and p53 (apoptosis canonical pathway), as well as induced autophagy. Whole genome analysis of treated MCF-7 cells showed a significant upregulation in gene expression in the autophagy, endoplasmic reticulum stress and the unfolded protein response apoptosis canonical pathways. Furthermore, MCF-7 cells treated with ATRA+D2+D3 demonstrated significant downregulation of gene expression in estrogen-mediated S phase entry and estrogen signaling canonical pathways suggesting antiestrogenic effects. 
Conclusions: Vitamins A and D combinations had synergistic effects in breast cancer cells and induced both apoptosis and autophagy. Transcriptional profiling showed significant alterations in gene expression patterns and upregulation of multiple cancer signaling pathways supporting the hypothesis that combining vitamins A and D is a more effective treatment than either vitamin alone. 

Keywords: all-trans-retinoic acid (ATRA), Vitamin D2, Vitamin D3, breast cancer cells, apoptosis, estrogen receptors

				
			
			

						
																																																																				
						
		


		

						
										
					
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																			2023-03-29
																	

				
							

			
						
										

											
							
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									Vol. 13 No. 3 (2023): March 2023
								
							

						
					
											
							
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