Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line

Abstract

Melanoma represents a significant challenge in cancer treatment due to the high drug resistance of melanomas and the patient mortality rate. This study presents data indicating that nanomolar concentrations of the hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], its non-calcemic analogues 20S-hydroxyvitamin D3 and 21-hydroxypregnacalciferol, as well as the low-calcemic synthetic analog calcipotriol, modulate the efficacy of the anticancer drugs cisplatin and dacarbazine. It was observed that vitamin D analogs sensitized melanoma A375 cells to hydrogen peroxide used as an inducer of oxidative stress. On the other hand, only 1α,25(OH)2D3 resulted in a minor, but significant effect on the proliferation of melanoma cells treated simultaneously with dacarbazine, but not cisplatin. Notably, cisplatin (300 µM) exhibited a higher overall antiproliferative activity than dacarbazine. Cisplatin treatment of melanoma cells resulted in an induction of apoptosis as demonstrated by flow cytometry (accumulation of cells at the subG1 phase of the cell cycle), whereas dacarbazine caused G1/G0 cell cycle arrest, with the effects being improved by pre-treatment with vitamin D analogs. Treatment with cisplatin resulted in an initial increase in the level of reactive oxygen species (ROS). Dacarbazine caused transient stimulation of ROS levels and the mitochondrial membrane potential (Δψm) (after 1 or 3 h of treatment, respectively), but the effect was not detectable following prolonged (24 h) incubation with the drug. Vitamin D exhibited modulatory effects on the cells treated with dacarbazine, decreasing the half maximal inhibitory concentration (IC50) for the drug, stimulating G1/G0 arrest and causing a marked decrease in Δψm. Finally, cisplatin, dacarbazine and 1α,25(OH)2D3 displayed modulatory effects on the expression of ROS and vitamin D-associated genes in the melanoma A375 cells. In conclusion, nanomolar concentrations of 1,25(OH)2D3 only had minor effects on the proliferation of melanoma cells treated with dacarbazine, decreasing the relative IC50 value. However, co-treatment with vitamin D analogs resulted in the modulation of cell cycle and ROS responses, and affected gene expression, suggesting possible crosstalk between the signaling pathways of vitamin D and the anticancer drugs used in this study.

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

“…It is worth mentioning that CP can promote ROS levels in mediating cell death in cancer cells. However, when an anti-tumor agent, such as vitamin D is co-administered with CP, its potential in enhancing ROS levels enhances [234]. Furthermore, a combination of CP with other anti-tumor compounds provide conditions for suppressing molecular pathways that can enhance cancer progression.…”

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

“…Furthermore, as revealed by analysis of transcriptome of melanoma patients, VDR expression was independently protective for melanomarelated death in both primary and metastatic disease (27). What is more, it was shown that active forms of vitamin D improve efficacy of several anticancer drugs, such as cisplatin (28,29), dacarbazine (30), doxorubicin (31), and proton therapy (32). It is also suggested that vitamin D immune-modulating ability could offer indications for a novel vitamin D application in melanoma patients receiving immunotherapy (33).…”

Transcriptomic Profiling Revealed Plexin A2 Downregulation With Migration and Invasion Alteration in Dacarbazine-Treated Primary Melanoma Cells

“…However, the overall response rate to DTIC rarely exceeds 17.6% ( 4 , 5 ). Mechanistically, DTIC is an alkylating agent that promotes G 1 -phase cell cycle arrest ( 6 ). Alkylating agents favor the formation of O6-alkylguanine derivatives, which bind to thymine instead of cytosine during DNA replication, thereby blocking cell division and causing cell death at the G 1 and S phases ( 7 ).…”