Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs
Melanoma is considered a lethal and treatment-resistant skin cancer with a high risk of recurrence, making it a major clinical challenge. Our earlier studies documented that 1,25(OH)<sub>2</sub>D<sub>3</sub> and its low-calcaemic analogues potentiate the effectiveness of daca...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8037 |
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| author | Anna Piotrowska Renata Zaucha Oliwia Król Michał Aleksander Żmijewski |
| author_facet | Anna Piotrowska Renata Zaucha Oliwia Król Michał Aleksander Żmijewski |
| author_sort | Anna Piotrowska |
| collection | DOAJ |
| description | Melanoma is considered a lethal and treatment-resistant skin cancer with a high risk of recurrence, making it a major clinical challenge. Our earlier studies documented that 1,25(OH)<sub>2</sub>D<sub>3</sub> and its low-calcaemic analogues potentiate the effectiveness of dacarbazine and cediranib, a pan-VEGFR inhibitor. In the current study, a set of patient-derived melanoma cultures was established and characterised as a preclinical model of human melanoma. Thus, patient-derived cells were preconditioned with 1,25(OH)<sub>2</sub>D<sub>3</sub> and treated with cediranib or vemurafenib, a BRAF inhibitor, depending on the BRAF mutation status of the patients enrolled in the study. 1,25(OH)<sub>2</sub>D<sub>3</sub> preconditioning exacerbated the inhibition of patient-derived melanoma cell growth and motility in comparison to monotherapy with cediranib. A significant decrease in mitochondrial respiration parameters, such as non-mitochondrial oxygen consumption, basal respiration and ATP-linked respiration, was observed. It seems that 1,25(OH)<sub>2</sub>D<sub>3</sub> preconditioning enhanced cediranib efficacy via the modulation of mitochondrial bioenergetics. Additionally, 1,25(OH)<sub>2</sub>D<sub>3</sub> also decreased the viability and mobility of the BRAF+ patient-derived cells treated with vemurafenib. Interestingly, regardless of the strict selection, cancer-derived fibroblasts (CAFs) became the major fraction of cultured cells over time, suggesting that melanoma growth is dependent on CAFs. In conclusion, the results of our study strongly emphasise that the active form of vitamin D, 1,25(OH)<sub>2</sub>D<sub>3</sub>, might be considered as an adjuvant agent in the treatment of malignant melanoma. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:17:37Z |
| publishDate | 2023-04-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e713acd833104d4cb387ccdc0c6c4a2b2023-11-17T23:04:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01249803710.3390/ijms24098037Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer DrugsAnna Piotrowska0Renata Zaucha1Oliwia Król2Michał Aleksander Żmijewski3Department of Histology, Faculty of Medicine, Medical University of Gdańsk, 80-211 Gdańsk, PolandDepartment of Oncology and Radiotherapy, Faculty of Medicine, Medical University of Gdańsk, 80-214 Gdańsk, PolandDepartment of Biochemistry, Faculty of Medicine, Medical University of Gdańsk, 80-211 Gdańsk, PolandDepartment of Histology, Faculty of Medicine, Medical University of Gdańsk, 80-211 Gdańsk, PolandMelanoma is considered a lethal and treatment-resistant skin cancer with a high risk of recurrence, making it a major clinical challenge. Our earlier studies documented that 1,25(OH)<sub>2</sub>D<sub>3</sub> and its low-calcaemic analogues potentiate the effectiveness of dacarbazine and cediranib, a pan-VEGFR inhibitor. In the current study, a set of patient-derived melanoma cultures was established and characterised as a preclinical model of human melanoma. Thus, patient-derived cells were preconditioned with 1,25(OH)<sub>2</sub>D<sub>3</sub> and treated with cediranib or vemurafenib, a BRAF inhibitor, depending on the BRAF mutation status of the patients enrolled in the study. 1,25(OH)<sub>2</sub>D<sub>3</sub> preconditioning exacerbated the inhibition of patient-derived melanoma cell growth and motility in comparison to monotherapy with cediranib. A significant decrease in mitochondrial respiration parameters, such as non-mitochondrial oxygen consumption, basal respiration and ATP-linked respiration, was observed. It seems that 1,25(OH)<sub>2</sub>D<sub>3</sub> preconditioning enhanced cediranib efficacy via the modulation of mitochondrial bioenergetics. Additionally, 1,25(OH)<sub>2</sub>D<sub>3</sub> also decreased the viability and mobility of the BRAF+ patient-derived cells treated with vemurafenib. Interestingly, regardless of the strict selection, cancer-derived fibroblasts (CAFs) became the major fraction of cultured cells over time, suggesting that melanoma growth is dependent on CAFs. In conclusion, the results of our study strongly emphasise that the active form of vitamin D, 1,25(OH)<sub>2</sub>D<sub>3</sub>, might be considered as an adjuvant agent in the treatment of malignant melanoma.https://www.mdpi.com/1422-0067/24/9/8037melanomavitamin Danti-angiogenic therapycediranibBRAF inhibitorsvemurafenib |
| spellingShingle | Anna Piotrowska Renata Zaucha Oliwia Król Michał Aleksander Żmijewski Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs International Journal of Molecular Sciences melanoma vitamin D anti-angiogenic therapy cediranib BRAF inhibitors vemurafenib |
| title | Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs |
| title_full | Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs |
| title_fullStr | Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs |
| title_full_unstemmed | Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs |
| title_short | Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs |
| title_sort | vitamin d modulates the response of patient derived metastatic melanoma cells to anticancer drugs |
| topic | melanoma vitamin D anti-angiogenic therapy cediranib BRAF inhibitors vemurafenib |
| url | https://www.mdpi.com/1422-0067/24/9/8037 |
| work_keys_str_mv | AT annapiotrowska vitamindmodulatestheresponseofpatientderivedmetastaticmelanomacellstoanticancerdrugs AT renatazaucha vitamindmodulatestheresponseofpatientderivedmetastaticmelanomacellstoanticancerdrugs AT oliwiakrol vitamindmodulatestheresponseofpatientderivedmetastaticmelanomacellstoanticancerdrugs AT michałaleksanderzmijewski vitamindmodulatestheresponseofpatientderivedmetastaticmelanomacellstoanticancerdrugs |