Kolorektal Kanser Tedavisinde Kalsitriol Kullanımı

Yıl 2026, Cilt: 16 Sayı: 1, 311 - 326, 01.03.2026

Sinem Tunçer Çağlayan

https://doi.org/10.21597/jist.1654927

https://izlik.org/JA33DL59UN

Öz

Kanda daha yüksek konsantrasyonda bulunması ve daha uzun yarılanma ömrü nedeniyle nedeniyle vücut vitamin D (vitD) düzeyini belirlemede vitD’nin ara metaboliti olan kalsidiol değerleri temel alınır. Serum kalsidiol seviyesi ile kanser ilişkisi ilk kez kolorektal kanserde (CRC)’de ortaya konmuş olup, devam eden çalışmalarda düşük kalsidiol düzeyleri ile CRC’nin yanı sıra, meme, prostat, akciğer, mesane, gastrik ve hemotolojik kanserler için yüksek risk ve kötü prognoz ilişkisi gösterilmiştir. Ancak, CRC ile ilgili olmak üzere yürütülen klinik çalışmalarda, vitD takviyesinin kanser oluşum riskini düşürdüğü ya da hastalığın ilerlemesi/prognozu süreçlerinde olumlu katkısını gösterir kuvvetli bulgular elde edilememiştir. Bu çalışmada CRC’de vitD yerine, aktif formu olan kalsitriol kullanımının avantajlı olabileceğini öne süren veriler ortaya konmakta ayrıca kalsitriolün farmasötik kullanımındaki kısıtlara işaret edilmektedir. Dolayısıyla, amaca uygun ve yenilikçi olarak tasarlanan taşıyıcı platformlar, gerek vitD eksikliği/yetersizliği gerekse anti-kanser etki için kalsitriol faydalanımını arttırabilir.

Anahtar Kelimeler

Vitamin D , Kalsitriol , Kanser

Etik Beyan

Bu çalışmada etik kurul iznine gerek duyulmamaktadır.

Destekleyen Kurum

TÜBİTAK

Proje Numarası

223S776

Teşekkür

CRC'de kalsitriolün anti-kanser etkinliğini araştıran çalışma, TÜBİTAK-ARDEB 1001 programı (Proje No: 223S776) tarafından desteklenmektedir.

Use of Calcitriol in Colorectal Cancer Treatment

https://izlik.org/JA33DL59UN

Öz

Due to its higher concentration in the blood and longer half-life calcidiol, the intermediate metabolite of vitamin D, is used as the main marker for determining vitamin D levels in the body. The relationship between serum calcidiol levels and cancer was first demonstrated in colorectal cancer (CRC), and subsequent studies have shown a link between low calcidiol levels and a higher risk and poor prognosis not only for CRC but also for breast, prostate, lung, bladder, gastric, and hematological cancers. However, clinical studies related to CRC have not provided strong evidence that vitamin D supplementation reduces cancer risk or positively impacts disease progression or prognosis. This study suggests that administration of calcitriol, the active form of vitamin D, may be more advantageous than vitamin D supplementation in CRC. It also points to the limitations of calcitriol in pharmaceutical applications. Therefore, appropriately designed and innovative carrier platforms could enhance the utilization of calcitriol for both vitamin D deficiency/insufficiency and its anti-cancer effects.

Anahtar Kelimeler

Vitamin D , Calcitriol , Cancer

Etik Beyan

Ethical approval is not required for this study.

Destekleyen Kurum

TÜBİTAK

Proje Numarası

223S776

Teşekkür

The study investigating the anticancer efficacy of calcitriol in CRC is supported by the TÜBİTAK-ARDEB 1001 program (Project No: 223S776).

Kaynakça

• Abu el Maaty, Mohamed A., and Stefan Wölfl. 2017. Vitamin D as a Novel Regulator of Tumor Metabolism: Insights on Potential Mechanisms and Implications for Anti-Cancer Therapy. International Journal of Molecular Sciences. doi:10.3390/ijms18102184.
• Almouazen, Eyad, Sandrine Bourgeois, Lars Petter Jordheim, Hatem Fessi, and Stephanie Briançon. 2013. Nano-Encapsulation of Vitamin D3 Active Metabolites for Application in Chemotherapy: Formulation Study and in Vitro Evaluation. Pharmaceutical Research 30 (4):1137–1146. doi:10.1007/s11095-012-0949-4.
• Ammar, Mariem, Syrine Heni, Mohamed Sahbi Tira, Yassine Khalij, Haithem Hamdouni, Dorra Amor, Sonia Ksibi, Asma Omezzine, and Ali Bouslama. 2022. Variability in Response to Vitamin D Supplementation According to Vitamin D Metabolism Related Gene Polymorphisms in Healthy Adults. European Journal of Clinical Nutrition 25 (September):1–6. doi:10.1038/s41430-022-01218-y.
• Bailie, George R., and Curtis A. Johnson. 2002. Comparative Review of the Pharmacokinetics of Vitamin D Analogues. Seminars in Dialysis 15 (5):352–357. doi:10.1046/j.1525-139x.2002.00086.x.
• Baron, John A., Elizabeth L. Barry, Leila A. Mott, Judy R. Rees, Robert S. Sandler, Dale C. Snover, Roberd M. Bostick, Anastasia Ivanova, Bernard F. Cole, Dennis J. Ahnen, et al. 2015. A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas. New England Journal of Medicine 373 (16):1519–1530. doi:10.1056/NEJMoa1500409.
• Brown, Ronald B. 2019. Vitamin D, Cancer, and Dysregulated Phosphate Metabolism. Endocrine 65 (2):238–243. doi:10.1007/s12020-019-01985-y.
• Carlberg, Carsten. 2022. Vitamin D and Its Target Genes. Nutrients 14 (7). doi:10.3390/nu14071354.
• Carlberg, Carsten, and Alberto Muñoz. 2022. An Update on Vitamin D Signaling and Cancer. Seminars in Cancer Biology 79 (February):217–230. doi:10.1016/j.semcancer.2020.05.018.
• Chang, Szu-Wen, and Hung-Chang Lee. 2019. Vitamin D and Health - The Missing Vitamin in Humans. Pediatrics & Neonatology 60 (3):237–244. doi:10.1016/j.pedneo.2019.04.007.
• Christakos, Sylvia, Shanshan Li, Jessica De La Cruz, and Daniel D. Bikle. 2019. New Developments in Our Understanding of Vitamin Metabolism, Action and Treatment. Metabolism: Clinical and Experimental. doi:10.1016/j.metabol.2019.06.010.
• Dědečková, Eva, Roman Viták, Michal Jirásko, Markéta Králová, Ondřej Topolčan, Ladislav Pecen, Tomáš Fürst, Pavel Brož, and Radek Kučera. 2023. Vitamin D3 Supplementation: Comparison of 1000 IU and 2000 IU Dose in Healthy Individuals. Life. doi:10.3390/life13030808.
• DeSmet, Marsha L., and James C. Fleet. 2017. Constitutively Active RAS Signaling Reduces 1,25 Dihydroxyvitamin D-Mediated Gene Transcription in Intestinal Epithelial Cells by Reducing Vitamin D Receptor Expression. The Journal of Steroid Biochemistry and Molecular Biology 173 (October):194–201. doi:10.1016/j.jsbmb.2017.01.008.
• Díaz, Lorenza, Mauricio Díaz-Muñoz, Ana García-Gaytán, and Isabel Méndez. 2015. Mechanistic Effects of Calcitriol in Cancer Biology. Nutrients 7 (6):5020–5050. doi:10.3390/nu7065020.
• Du, Jie, Xinzhi Wei, Xin Ge, Yinyin Chen, and Yan Chun Li. 2017. Microbiota-Dependent Induction of Colonic Cyp27b1 Is Associated With Colonic Inflammation: Implications of Locally Produced 1,25-Dihydroxyvitamin D3 in Inflammatory Regulation in the Colon. Endocrinology 158 (11):4064–4075. doi:10.1210/en.2017-00578.
• El-Sharkawy, Ahmed, and Ahmed Malki. 2020. Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications. Molecules 25 (14):3219. doi:10.3390/molecules25143219.
• Fan, Ziwei, Zhen Wang, Weiran Chen, Zhiwei Cao, and Yixue Li. 2016. Association between the CYP11 Family and Six Cancer Types. Oncology Letters. doi:10.3892/ol.2016.4567.
• Feldmann, Sir Marc. 2018. Cancer Immunotherapy in Routine Cost-Effective Cancer Care? EMBO Molecular Medicine 10 (11). doi:10.15252/emmm.201809660.
• Fernández-Barral, Asunción, Alba Costales-Carrera, Sandra P. Buira, Peter Jung, Gemma Ferrer-Mayorga, María Jesús Larriba, Pilar Bustamante-Madrid, Orlando Domínguez, Francisco X. Real, Laura Guerra-Pastrián, et al. 2020. Vitamin D Differentially Regulates Colon Stem Cells in Patient-Derived Normal and Tumor Organoids. FEBS Journal. doi:10.1111/febs.14998.
• Ferrer-Mayorga, Gemma, María Jesús Larriba, Piero Crespo, and Alberto Muñoz. 2019. Mechanisms of Action of Vitamin D in Colon Cancer. The Journal of Steroid Biochemistry and Molecular Biology 185 (January):1–6. doi:10.1016/j.jsbmb.2018.07.002.
• Garland, Cedric F., Edward D. Gorham, Sharif B. Mohr, and Frank C. Garland. 2009. Vitamin D for Cancer Prevention: Global Perspective. Annals of Epidemiology 19 (7):468–483. doi:10.1016/j.annepidem.2009.03.021.
• Gesmundo, Iacopo, Francesca Silvagno, Dana Banfi, Valentina Monica, Alessandro Fanciulli, Giacomo Gamba, Noemi Congiusta, Roberta Libener, Chiara Riganti, Ezio Ghigo, et al. 2020. Calcitriol Inhibits Viability and Proliferation in Human Malignant Pleural Mesothelioma Cells. Frontiers in Endocrinology 11 (October). doi:10.3389/fendo.2020.559586.
• Gkotinakou, Ioanna-Maria, Eleni Kechagia, Kalliopi Pazaitou-Panayiotou, Ilias Mylonis, Panagiotis Liakos, and Andreas Tsakalof. 2020. Calcitriol Suppresses HIF-1 and HIF-2 Transcriptional Activity by Reducing HIF-1/2α Protein Levels via a VDR-Independent Mechanism. Cells 9 (11):2440. doi:10.3390/cells9112440.
• Haussler, Mark R, G. Kerr Whitfield, Carol A. Haussler, Marya S. Sabir, Zainab Khan, Ruby Sandoval, and Peter W. Jurutka. 2016. 1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age. Vitamins and Hormones 100:165–230. doi:10.1016/bs.vh.2015.11.005.
• Hii, Charles, and Antonio Ferrante. 2016. The Non-Genomic Actions of Vitamin D. Nutrients 8 (3):135. doi:10.3390/nu8030135.
• Huang, Chun-Yin, Yu-Ting Weng, Po-Chen Li, Nien-Tsu Hsieh, Chun-I Li, Hsiao-Sheng Liu, and Ming-Fen Lee. 2021. Calcitriol Suppresses Warburg Effect and Cell Growth in Human Colorectal Cancer Cells. Life 11 (9):963. doi:10.3390/life11090963.
• Hummel, Doris M., Irfete S. Fetahu, Charlotte Gröschel, Teresa Manhardt, and Eniko Kállay. 2014. Role of Proinflammatory Cytokines on Expression of Vitamin D Metabolism and Target Genes in Colon Cancer Cells. Journal of Steroid Biochemistry and Molecular Biology. doi:10.1016/j.jsbmb.2013.09.017.
• Jacobs, Elizabeth T., Chad Van Pelt, Ryan E. Forster, Wasiq Zaidi, Elizabeth A. Hibler, Michael A. Galligan, Mark R. Haussler, and Peter W. Jurutka. 2013. CYP24A1 and CYP27B1 Polymorphisms Modulate Vitamin D Metabolism in Colon Cancer Cells. Cancer Research 73 (8):2563–2573. doi:10.1158/0008-5472.CAN-12-4134.
• Javed, Moiz, Aldanah Althwanay, Farah Ahsan, Federico Oliveri, Harshit K Goud, Zainab Mehkari, Lubna Mohammed, and Ian H Rutkofsky. 2020. Role of Vitamin D in Colorectal Cancer: A Holistic Approach and Review of the Clinical Utility. Cureus. doi:10.7759/cureus.10734.
• Jeon, Sang-Min, and Eun-Ae Shin. 2018. Exploring Vitamin D Metabolism and Function in Cancer. Experimental & Molecular Medicine 50 (4):1–14. doi:10.1038/s12276-018-0038-9.
• Jiang, Xia, Douglas P. Kiel, and Peter Kraft. 2019. The Genetics of Vitamin D. Bone 126 (September):59–77. doi:10.1016/j.bone.2018.10.006.
• Karaçam, Sevinç, and Sinem Tunçer. 2022. Exploiting the Acidic Extracellular PH: Evaluation of Streptococcus Salivarius M18 Postbiotics to Target Cancer Cells. Probiotics and Antimicrobial Proteins 14 (6):995–1011. doi:10.1007/s12602-021-09806-3.
• Koivisto, Oona, Andrea Hanel, and Carsten Carlberg. 2020. Key Vitamin D Target Genes with Functions in the Immune System. Nutrients. doi:10.3390/nu12041140.
• Kósa, János P. 2013. CYP24A1 Inhibition Facilitates the Anti-Tumor Effect of Vitamin D3 on Colorectal Cancer Cells. World Journal of Gastroenterology 19 (17):2621. doi:10.3748/wjg.v19.i17.2621.
• Mazahery, Hajar, and Pamela R von Hurst. 2015. Factors Affecting 25-Hydroxyvitamin D Concentration in Response to Vitamin D Supplementation. Nutrients 7 (7):5111–5142. doi:10.3390/nu7075111.
• Na, Soo-Young, Ki Bae Kim, Yun Jeong Lim, and Hyun Joo Song. 2022. Vitamin D and Colorectal Cancer: Current Perspectives and Future Directions. Journal of Cancer Prevention. doi:10.15430/jcp.2022.27.3.147.
• Ng K et al. 2024. LBA26 - SOLARIS (Alliance A021703): A Multicenter Double-Blind Phase III Randomized Clinical Trial (RCT) of Vitamin D (VitD) Combined with Standard Chemotherapy plus Bevacizumab (Bev) in Patients (Pts) with Previously Untreated Metastatic Colorectal Cance. Annals of Oncology 35 (suppl_:1–72. doi:10.1016/annonc/annonc1623.
• Ng, Kimmie, Halla S. Nimeiri, Nadine J. McCleary, Thomas A. Abrams, Matthew B. Yurgelun, James M. Cleary, Douglas A. Rubinson, Deborah Schrag, Rebecca Miksad, Andrea J. Bullock, et al. 2019. Effect of High-Dose vs Standard-Dose Vitamin D 3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer. JAMA 321 (14):1370. doi:10.1001/jama.2019.2402.
• Nicolas, Sabrina, Marie-Alexandrine Bolzinger, Lars Petter Jordheim, Yves Chevalier, Hatem Fessi, and Eyad Almouazen. 2018. Polymeric Nanocapsules as Drug Carriers for Sustained Anticancer Activity of Calcitriol in Breast Cancer Cells. International Journal of Pharmaceutics 550 (1–2):170–179. doi:10.1016/j.ijpharm.2018.08.022.
• Öncül Börekçi, Nazire. 2019. Current Information on Vitamin D Deficiency. The Journal of Turkish Family Physician 10 (1):35–42. doi:10.15511/jtfp.19.00135.
• Padi, Sathish K.R., Qunshu Zhang, Youcef M. Rustum, Carl Morrison, and Bin Guo. 2013. MicroRNA-627 Mediates the Epigenetic Mechanisms of Vitamin d to Suppress Proliferation of Human Colorectal Cancer Cells and Growth of Xenograft Tumors in Mice. Gastroenterology. doi:10.1053/j.gastro.2013.04.012.
• Peixoto, Renata D.Alpino, Leandro Jonata de Carvalho Oliveira, Thaís de Melo Passarini, Aline Chaves Andrade, Paulo Henrique Diniz, Gabriel Prolla, Larissa Costa Amorim, Mariana Gil, Flora Lino, Bernardo Garicochea, et al. 2022. Vitamin D and Colorectal Cancer – A Practical Review of the Literature. Cancer Treatment and Research Communications 32:100616. doi:10.1016/j.ctarc.2022.100616.
• Ramalho, Maria J., Joana A. Loureiro, Bárbara Gomes, Manuela F. Frasco, Manuel A N Coelho, and M Carmo Pereira. 2015. PLGA Nanoparticles as a Platform for Vitamin D-Based Cancer Therapy. Beilstein Journal of Nanotechnology 6 (June):1306–1318. doi:10.3762/bjnano.6.135.
• Schroll, Monica M., Katelyn R. Ludwig, Kerry M. Bauer, and Amanda B. Hummon. 2018. Calcitriol Supplementation Causes Decreases in Tumorigenic Proteins and Different Proteomic and Metabolomic Signatures in Right versus Left-Sided Colon Cancer. Metabolites. doi:10.3390/metabo8010005.
• Song, Mingyang, I-Min Lee, Joann E. Manson, Julie E. Buring, Rimma Dushkes, David Gordon, Joseph Walter, Kana Wu, Andrew T. Chan, Shuji Ogino, et al. 2020. Effect of Supplementation With Marine ω-3 Fatty Acid on Risk of Colorectal Adenomas and Serrated Polyps in the US General Population. JAMA Oncology 6 (1):108. doi:10.1001/jamaoncol.2019.4587.
• Sun, Hongyan, Chuanwen Wang, Miao Hao, Ran Sun, Yuqian Wang, Tie Liu, Xianling Cong, and Ya Liu. 2016. CYP24A1 Is a Potential Biomarker for the Progression and Prognosis of Human Colorectal Cancer. Human Pathology. doi:10.1016/j.humpath.2015.11.008.
• Sun, Jun. 2017. The Role of Vitamin D and Vitamin D Receptors in Colon Cancer. Clinical and Translational Gastroenterology. doi:10.1038/ctg.2017.31.
• Trump, Donald L. 2018. Calcitriol and Cancer Therapy: A Missed Opportunity. Bone Reports 9 (December):110–119. doi:10.1016/j.bonr.2018.06.002.
• Trump, Donald L., Pamela A. Hershberger, Ronald J. Bernardi, Sharmilla Ahmed, Josephia Muindi, Marwan Fakih, Wei-Dong Yu, and Candace S. Johnson. 2004. Anti-Tumor Activity of Calcitriol: Pre-Clinical and Clinical Studies. The Journal of Steroid Biochemistry and Molecular Biology 89–90 (May):519–526. doi:10.1016/j.jsbmb.2004.03.068.
• Tunçer, S., S. Tunçay Çağatay, A.G. Keşküş, M. Çolakoğlu, Ö. Konu, and S. Banerjee. 2016. Interplay between 15‐lipoxygenase‐1 and Metastasis‐associated Antigen 1 in the Metastatic Potential of Colorectal Cancer. Cell Proliferation 49 (4):448–459. doi:10.1111/cpr.12267.
• Turunen, Mikko M., Thomas W. Dunlop, Carsten Carlberg, and S. Vaisanen. 2007. Selective Use of Multiple Vitamin D Response Elements Underlies the 1 ,25-Dihydroxyvitamin D3-Mediated Negative Regulation of the Human CYP27B1 Gene. Nucleic Acids Research 35 (8):2734–2747. doi:10.1093/nar/gkm179.
• Urashima, Mitsuyoshi, Hironori Ohdaira, Taisuke Akutsu, Shinya Okada, Masashi Yoshida, Masaki Kitajima, and Yutaka Suzuki. 2019. Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers. JAMA 321 (14):1361. doi:10.1001/jama.2019.2210.
• Vaughan-Shaw, Peter G, James P. Blackmur, Graeme Grimes, Li‐Yin Ooi, Anna M Ochocka-Fox, Karen Dunbar, Alex von Kriegsheim, Vidya Rajasekaran, Maria Timofeeva, Marion Walker, et al. 2022. Vitamin D Treatment Induces in Vitro and Ex Vivo Transcriptomic Changes Indicating Anti-Tumor Effects. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 36 (1):e22082. doi:10.1096/fj.202101430RR.
• Wactawski-Wende, Jean, Jane Morley Kotchen, Garnet L. Anderson, Annlouise R. Assaf, Robert L. Brunner, Mary Jo O’Sullivan, Karen L. Margolis, Judith K. Ockene, Lawrence Phillips, Linda Pottern, et al. 2006. Calcium plus Vitamin D Supplementation and the Risk of Colorectal Cancer. New England Journal of Medicine. doi:10.1056/nejmoa055222.
• Wang, Ke, Ruoyu Shen, Tingting Meng, Fuqiang Hu, and Hong Yuan. 2022. Nano-Drug Delivery Systems Based on Different Targeting Mechanisms in the Targeted Therapy of Colorectal Cancer. Molecules (Basel, Switzerland) 27 (9):2981. doi:10.3390/molecules27092981.
• Waterhouse, Mary, Bich Tran, Bruce K. Armstrong, Catherine Baxter, Peter R. Ebeling, Dallas R. English, Val Gebski, Christine Hill, Michael G. Kimlin, Robyn M. Lucas, et al. 2014. Environmental, Personal, and Genetic Determinants of Response to Vitamin D Supplementation in Older Adults. The Journal of Clinical Endocrinology and Metabolism 99 (7):E1332-40. doi:10.1210/jc.2013-4101.
• Wei, Jia, Anna Zhu, and John S. Ji. 2019. A Comparison Study of Vitamin D Deficiency among Older Adults in China and the United States. Scientific Reports 9 (1):19713. doi:10.1038/s41598-019-56297-y.
• Weng, Junyong, Shanbao Li, Zhonglin Zhu, Qi Liu, Ruoxin Zhang, Yufei Yang, and Xinxiang Li. 2022. Exploring Immunotherapy in Colorectal Cancer. Journal of Hematology & Oncology 15 (1):95. doi:10.1186/s13045-022-01294-4.
• Wootton, Andrew M. 2005. Improving the Measurement of 25-Hydroxyvitamin D. The Clinical Biochemist. Reviews.
• Yuan, Ting, Lingzhen Qin, Zhouhua Wang, Jinyuan Nie, Zhefei Guo, Ge Li, and Chuanbin Wu. 2013. Solid Lipid Dispersion of Calcitriol with Enhanced Dissolution and Stability. Asian Journal of Pharmaceutical Sciences 8 (1):39–47. doi:10.1016/j.ajps.2013.07.005.
• Yue, Xiao, Yingtong Cui, Ting Yuan, Zhengwei Huang, Ying Huang, Xuejuan Zhang, Chen Wang, Guanlin Wang, Ruifeng Liang, Chunxia Liu, et al. 2020. Calcitriol Tablets with Hybrid Lipid-Based Solid Dispersions with Enhanced Stability and Content Uniformity. Pharmaceutical Development and Technology. doi:10.1080/10837450.2020.1760297.
• Zhu, Chaojun, Zihuan Wang, Jianqun Cai, Chunqiu Pan, Simin Lin, Yue Zhang, Yuting Chen, Mengxin Leng, Chengcheng He, Peirong Zhou, et al. 2021. VDR Signaling via the Enzyme NAT2 Inhibits Colorectal Cancer Progression. Frontiers in Pharmacology. doi:10.3389/fphar.2021.727704.