Vitamin D Modulates the Response of Patient-Derived Metastatic Melanoma Cells to Anticancer Drugs

Abstract

Melanoma is considered a lethal and treatment-resistant skin cancer with a high risk of recurrence, making it is a major clinical challenge. Our earlier studies documented that 1,25(OH)2D3 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)2D3 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)2D3 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)2D3 preconditioning enhanced cediranib efficacy via the modulation of mitochondrial bioenergetics. Additionally, 1,25(OH)2D3 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)2D3, might be considered as an adjuvant agent in the treatment of malignant melanoma.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling

“…Relating to murine B16 melanoma, the reported differences in biological effects of vitamin D derivatives could be secondary to test conditions or simply use of different sublines of B16 melanoma [ 588 ]. A variety of vitamin D3 and D2 derivatives were tested including classical forms, chemically generated low calcemic forms, and CYP11A1-derived non-calcemic or low calcemic variants, all of them showing anti-melanoma activities on cultured melanoma cells [ 51 , 63 , 188 , 285 , 410 , 411 , 439 , 441 , 443 , 449 , 461 , 483 , 484 , 487 , 489 , 533 , 569 , 588 , 593 , 594 , 595 , 596 , 597 ]. In some melanomas, 1,25(OH) 2 D3 or its synthetic analogs showed proapoptotic effects, while in others there was a lack of such effect [ 188 , 598 ].…”

“…Vitamin D derivatives not only have a direct anti-melanoma effect, but also can sensitize melanoma cells to different types of therapy [ 592 , 594 , 595 , 596 , 601 ]. For example, 1,25(OH) 2 D3 and 25(OH)D3 can sensitize melanoma towards proton beam therapy [ 601 ].…”

“…For example, 1,25(OH) 2 D3 and 25(OH)D3 can sensitize melanoma towards proton beam therapy [ 601 ]. In human melanomas in culture, they modulate anticancer properties of cisplatin and dacarbazine [ 594 ], and enhance anticancer properties of cediranib, a VEGFR inhibitor [ 596 ], and of vemurafenib [ 595 ]. Concerning the relationship between melanogenesis and vitamin D, it has been shown that the amelanotic phenotype makes melanoma cells more sensitive to active forms of vitamin D in comparison to melanotic ones [ 411 ].…”

Protein Disulfide Isomerase Family A Member 3 Knockout Abrogate Effects of Vitamin D on Cellular Respiration and Glycolysis in Squamous Cell Carcinoma

“…However, several studies have shown the direct effects of 1,25(OH) 2 D 3 on ion transport [31,32], including activity of mitochondrial membrane potassium channels [33]. Finally, pre-incubation with 1,25(OH) 2 D 3 significantly deepened the effect of anti-cancer drugs on the mitochondrial respiration of patient-derived melanoma cells [34].…”

Fibroblast Growth Factor Receptor Inhibitors Decrease Proliferation of Melanoma Cell Lines and Their Activity Is Modulated by Vitamin D

“…Additionally, we have also explored whether 1,25(OH) 2 D 3 modulates the effectiveness of selected drugs, since we have shown that vitamin D and its analogue, calcipotriol, enhance the activity of a classical chemotherapeutic, dacarbazine, in human malignant A375 melanoma cell line [ 20 ]. Recently we also showed that 1,25(OH) 2 D 3 and other vitamin D derivatives significantly augment the efficacy of cediranib, an oral tyrosine kinase inhibitor of VEGFR1-3, PDGFR, and c-KIT, against A375 and SK-MEL-28 melanoma cell lines, out of four human cell lines that were tested, as well as against patient-derived melanoma cells [ 21 , 22 ]. What is more, there is a clear link between FGFRs signalling and vitamin D homeostasis, as loss of function in FGFRs leads to deregulation of Cyp27b1 and Cyp24a1 and the induction of hypervitaminosis D in a mouse model [ 23 ].…”