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

Anna Piotrowska, Justyna Wierzbicka, Agnieszka Rybarczyk, Robert C. Tuckey, Andrzej T. Slominski, Michal A. Zmijewski

Research output: Contribution to journalArticle

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, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)(2)D3], 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 1 alpha,25(OH)(2)D3 resulted in a minor, but significant effect on the proliferation of melanoma cells treated simultaneously with dacarbazine, but not cisplatin. Notably, cisplatin (300 mu M) 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 subG(1) phase of the cell cycle), whereas dacarbazine caused G(1)/G(0) 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 (Delta psi(m)) (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 G(1)/G(0) arrest and causing a marked decrease in Delta psi(m). Finally, cisplatin, dacarbazine and 1 alpha,25(OH)(2)D3 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)(2)D-3 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.

Original languageEnglish
Pages (from-to)1481-1495
Number of pages15
JournalInternational Journal of Oncology
Volume54
Issue number4
DOIs
Publication statusPublished - Apr 2019

Cite this

Piotrowska, Anna ; Wierzbicka, Justyna ; Rybarczyk, Agnieszka ; Tuckey, Robert C. ; Slominski, Andrzej T. ; Zmijewski, Michal A. / Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line. In: International Journal of Oncology. 2019 ; Vol. 54, No. 4. pp. 1481-1495.
@article{d034c7ee1b084a1499124c15104959fb,
title = "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, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)(2)D3], 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 1 alpha,25(OH)(2)D3 resulted in a minor, but significant effect on the proliferation of melanoma cells treated simultaneously with dacarbazine, but not cisplatin. Notably, cisplatin (300 mu M) 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 subG(1) phase of the cell cycle), whereas dacarbazine caused G(1)/G(0) 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 (Delta psi(m)) (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 G(1)/G(0) arrest and causing a marked decrease in Delta psi(m). Finally, cisplatin, dacarbazine and 1 alpha,25(OH)(2)D3 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)(2)D-3 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.",
keywords = "vitamin D, vitamin D analogs, hydroxyvitamin D, melanoma, reactive oxygen species, oxidative stress, cisplatin, dacarbazine, chemotherapy, EMERGING TARGETED THERAPIES, DNA-DAMAGE, 25-HYDROXYVITAMIN D, BREAST-CANCER, IN-VITRO, SKIN, EXPRESSION, PROLIFERATION, PROGRESSION, CALCITRIOL",
author = "Anna Piotrowska and Justyna Wierzbicka and Agnieszka Rybarczyk and Tuckey, {Robert C.} and Slominski, {Andrzej T.} and Zmijewski, {Michal A.}",
year = "2019",
month = "4",
doi = "10.3892/ijo.2019.4725",
language = "English",
volume = "54",
pages = "1481--1495",
journal = "International Journal of Oncology",
issn = "1019-6439",
publisher = "SPANDIDOS PUBL LTD",
number = "4",

}

Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line. / Piotrowska, Anna; Wierzbicka, Justyna; Rybarczyk, Agnieszka; Tuckey, Robert C.; Slominski, Andrzej T.; Zmijewski, Michal A.

In: International Journal of Oncology, Vol. 54, No. 4, 04.2019, p. 1481-1495.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line

AU - Piotrowska, Anna

AU - Wierzbicka, Justyna

AU - Rybarczyk, Agnieszka

AU - Tuckey, Robert C.

AU - Slominski, Andrzej T.

AU - Zmijewski, Michal A.

PY - 2019/4

Y1 - 2019/4

N2 - 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, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)(2)D3], 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 1 alpha,25(OH)(2)D3 resulted in a minor, but significant effect on the proliferation of melanoma cells treated simultaneously with dacarbazine, but not cisplatin. Notably, cisplatin (300 mu M) 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 subG(1) phase of the cell cycle), whereas dacarbazine caused G(1)/G(0) 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 (Delta psi(m)) (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 G(1)/G(0) arrest and causing a marked decrease in Delta psi(m). Finally, cisplatin, dacarbazine and 1 alpha,25(OH)(2)D3 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)(2)D-3 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.

AB - 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, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)(2)D3], 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 1 alpha,25(OH)(2)D3 resulted in a minor, but significant effect on the proliferation of melanoma cells treated simultaneously with dacarbazine, but not cisplatin. Notably, cisplatin (300 mu M) 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 subG(1) phase of the cell cycle), whereas dacarbazine caused G(1)/G(0) 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 (Delta psi(m)) (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 G(1)/G(0) arrest and causing a marked decrease in Delta psi(m). Finally, cisplatin, dacarbazine and 1 alpha,25(OH)(2)D3 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)(2)D-3 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.

KW - vitamin D

KW - vitamin D analogs

KW - hydroxyvitamin D

KW - melanoma

KW - reactive oxygen species

KW - oxidative stress

KW - cisplatin

KW - dacarbazine

KW - chemotherapy

KW - EMERGING TARGETED THERAPIES

KW - DNA-DAMAGE

KW - 25-HYDROXYVITAMIN D

KW - BREAST-CANCER

KW - IN-VITRO

KW - SKIN

KW - EXPRESSION

KW - PROLIFERATION

KW - PROGRESSION

KW - CALCITRIOL

U2 - 10.3892/ijo.2019.4725

DO - 10.3892/ijo.2019.4725

M3 - Article

VL - 54

SP - 1481

EP - 1495

JO - International Journal of Oncology

JF - International Journal of Oncology

SN - 1019-6439

IS - 4

ER -