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.
Highlights
Melanoma, representing a minor fraction of all skin malignancies, remains the most lethal form [1, 2]
Since cediranib is a small-molecule inhibitor of several tyrosine kinases, including VEGFR1 and VEGFR2, of which the latter seems to play a predominant role [51], we investigated whether vitamin D preincubation will affect the extracellular expression of VEGFR2 in A375 melanoma cells exposed to cediranib
It is well documented that vitamin D protects against DNA damage [54, 55] and against UV-induced carcinogenesis [56,57,58], since UV is considered as the major environmental risk factor for melanoma development [47]
Summary
Representing a minor fraction of all skin malignancies, remains the most lethal form [1, 2]. Patients with advanced melanoma could expect a 5-year survival rate of 10% [3]. Regardless of the groundbreaking treatment options, most patients invariably relapse from BRAF/ MEK signaling inhibition within a year from treatment commencement [6]. About 50% of patients treated with immune checkpoints inhibitors do not respond due to primary resistance and a great proportion of responders experience tumor relapse within 2 years [7, 8]. Current 5-year survival rate for metastatic melanoma is 27% [9]. The incidence of melanoma is constantly rising worldwide, and currently, melanoma is expected to be the fifth most common cancer in both males and females, as estimated by the American Cancer Society [9]. It seems to be highly reasonable to focus on new combination strategies and adjuvant settings to improve melanoma patient outcomes [4]
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