Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line
Autor: | Justyna Wierzbicka, Michał A. Żmijewski, Agnieszka Rybarczyk, Andrzej Slominski, Anna Piotrowska, Robert C. Tuckey |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Vitamin
Cancer Research Skin Neoplasms Calcitriol Dacarbazine cisplatin Apoptosis vitamin D dacarbazine Biology Pharmacology chemotherapy 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 0302 clinical medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Vitamin D and neurology melanoma Humans oxidative stress 030304 developmental biology Cisplatin reactive oxygen species 0303 health sciences Melanoma hydroxyvitamin D Drug Synergism Articles Cell cycle medicine.disease G1 Phase Cell Cycle Checkpoints 3. Good health Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis vitamin D analogs medicine.drug |
Zdroj: | International Journal of Oncology |
ISSN: | 1791-2423 1019-6439 |
Popis: | 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. |
Databáze: | OpenAIRE |
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