Vitamin D Enhances Anticancer Properties of Cediranib, a VEGFR Inhibitor, by Modulation of VEGFR2 Expression in Melanoma Cells

Abstract

Regardless of the recent groundbreaking introduction of personalized therapy, melanoma continues to be one of the most lethal skin malignancies. Still, a substantial proportion of patients either fail to respond to the therapy or will relapse over time, representing a challenging clinical problem. Recently, we have shown that vitamin D enhances the effectiveness of classical chemotherapeutics in the human malignant melanoma A375 cell line. In search for new combination strategies and adjuvant settings to improve melanoma patient outcomes in the current study, the effects of cediranib (AZD2171), an oral tyrosine kinase inhibitor of VEGFR1-3, PDGFR, and c-KIT, used in combination either with 1,25(OH)2D3 or with low-calcemic analog calcipotriol were tested on four human malignant melanoma cell lines (A375, MNT-1, RPMI-7951, and SK-MEL-28). Melanoma cells were pretreated with vitamin D and subsequently exposed to cediranib. We observed a marked decrease in melanoma cell proliferation (A375 and SK-MEL-28), G2/M cell cycle arrest, and a significant decrease in melanoma cell mobility in experimental conditions used (A375). Surprisingly, concurrently with a very desirable decrease in melanoma cell proliferation and mobility, we noticed the upregulation of VEGFR2 at both protein and mRNA levels. No effect of vitamin D was observed in MNT-1 and RPMI-7951 melanoma cells. It seems that vitamin D derivatives enhance cediranib efficacy by modulation of VEGFR2 expression in melanoma cells expressing VEGFR2. In conclusion, our experiments demonstrated that vitamin D derivatives hold promise as novel adjuvant candidates to conquer melanoma, especially in patients suffering from vitamin D deficiency. However, further extensive research is indispensable to reliably assess their potential benefits for melanoma patients.

Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms

“…1,25-(OH) 2 D 3 alone and more strongly in combination with cisplatin suppresses VEGF activity in ovarian cancer cells [ 222 ]. By modulating VEGF receptor (VEGFR) 2, 1,25-(OH) 2 D 3 or calcipotriol, it enhances the efficacy of the VEGFR inhibitor Cediranib in malignant melanoma cells [ 223 ]. Another antiangiogenic mechanism of 1,25-(OH) 2 D 3 is the reduction of IL-8 secretion by prostate cancer cells through the inhibition of NF-κB [ 224 ].…”

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

“…To assess the effect of VEGFR tyrosine kinase inhibitor-cediranib [43] and 1,25(OH) 2 D 3 on the proliferation of patient-derived melanoma cells, 72 h long live imaging using the Olympus cell Vivo IX 83 microscope was performed. We used the same experimental conditions as in our previous study on cediranib (72 h simultaneous incubation of cells with cediranib and 1,25(OH) 2 D 3 at a 100 nM concentration), as these treatment regimens were highly efficient at inhibiting the growth of A375 melanoma cells [17]. In line with our expectations, the proliferation rate was the highest in non-treated control cells (Figure 3).…”

“…Our earlier research documented that 1,25(OH) 2 D 3 preconditioning modulated the mitochondrial transmembrane potential of A375 melanoma cells treated with the classic chemotherapeutics cisplatin and dacarbazine [30]. Additionally, our latest work documented that 1,25(OH) 2 D 3 enhances the cytotoxic effect of cediranib in A375 and SK-MEL-28 melanoma cells [17]. Therefore, in the next step of the current research, the effect of cediranib on mitochondrial membrane potential in 1,25(OH) 2 D 3 preconditioned patientderived melanoma cells was tested.…”

“…UV light, which is considered a major cause of melanoma, is also essential for vitamin D production in the skin [13][14][15][16][17]. This powerful secosteroid is most widely known as a regulator of calcium homeostasis in our body, but also shows antiproliferative, antiangiogenic and pro-differentiative properties against multiple types of cancer cells [13,18,19].…”

“…Our previous study documented that calcitriol (1,25(OH) 2 D 3 ), the biologically active form of vitamin D, as well as the low-calcaemic vitamin D analogue calcipotriol, enhanced the activity of dacarbazine in A375 melanoma cells [30]. Recently, we reported that both calcitriol and calcipotriol significantly enhanced the cytotoxicity of an antiangiogenic compound, cediranib, through the upregulation of VEGFR2, at both the protein and mRNA levels, in A375 and SK-MEL-28 melanoma cells [17]. In the current study, we expanded a panel of patient-derived melanoma cell cultures to test whether 1,25(OH) 2 D 3 would potentiate the anticancer properties of cediranib.…”