Cisplatin (cddp) triggers cell death of mcf-7 cells following disruption of intracellular calcium ([ca2+]i) homeostasis

Nawaf Al-Taweel, Elizabeth Varghese, Ana Maria Florea, Dietrich Busselberg

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Breast cancer (BC) is a public health problem all over the world. Cisplatin (CDDP) is an antineoplastic agent with high rate of success in treating cancers. The down side of CDDP treatment is the development of chemo-resistance. Beside DNA damage and activation of p53 signaling pathway, CDDP induces tumor-cell death due to elevation in the intracellular calcium concentration ([Ca2+]i). However, the role of [Ca2+]i in CDDP induced apoptosis of breast cancer cells (MCF-7) is not well understood. Here we investigate the cytotoxic effects of CDDP in relation to [Ca2+]i homeostasis in MCF-7-sen-sitive and -resistant cell lines. Live-cell imaging using [Ca2+]i sensitive fluorescent dyes was employed to monitor [Ca2+]i CDDP treated MCF-7 cells (0.001-10 μM) and [Ca2+]i modulators i.e. Caffeine (10 mM); Nimodipine (10 μM); Ionomycin (10 μM); Thapsigargin (500 nM). A concentration-dependent increase of [Ca2+]i was observed in CDDP MCF-7 treated cells. From the concentration range tested 100 nM CDDP triggered the highest [Ca2+]i increase (120%; n = 19) while in drug resistant MCF-7 cells the effects of CDDP on [Ca2+]i were reduced as compared with the drug sensitive MCF-7 cells. Furthermore, the CDDP induced cell death correlates with the increase of [Ca2+]i, and thus, significantly lower in the CDDP desensitized cells (p < 0.05). Pre-application of the calcium channel blocker, Nimodipine reduced [Ca2+]i elevation significantly (46.6% increase; n = 26) as well as when a pre-application of Caffeine, Ionomycin or Thapsigargin occurred followed by the subsequent application of CDDP (n = 15; 37.8%, n = 32; 34.9%, n = 21; 53.7% increase respectively).

Original languageEnglish
Pages (from-to)765-774
Number of pages10
JournalJournal of Toxicological Sciences
Volume39
Issue number5
DOIs
Publication statusPublished - 2014

Fingerprint

MCF-7 Cells
Cell death
Cisplatin
Nimodipine
Ionomycin
Homeostasis
Cell Death
Thapsigargin
Cells
Caffeine
Calcium
Calcium Channel Blockers
Public health
Medical problems
Fluorescent Dyes
Pharmaceutical Preparations
Antineoplastic Agents
Modulators
Tumors
Breast Neoplasms

Keywords

  • Breast cancer
  • Calcium signaling
  • Cisplatin
  • MCF-7
  • Tumor cell death

ASJC Scopus subject areas

  • Toxicology

Cite this

Cisplatin (cddp) triggers cell death of mcf-7 cells following disruption of intracellular calcium ([ca2+]i) homeostasis. / Al-Taweel, Nawaf; Varghese, Elizabeth; Florea, Ana Maria; Busselberg, Dietrich.

In: Journal of Toxicological Sciences, Vol. 39, No. 5, 2014, p. 765-774.

Research output: Contribution to journalArticle

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abstract = "Breast cancer (BC) is a public health problem all over the world. Cisplatin (CDDP) is an antineoplastic agent with high rate of success in treating cancers. The down side of CDDP treatment is the development of chemo-resistance. Beside DNA damage and activation of p53 signaling pathway, CDDP induces tumor-cell death due to elevation in the intracellular calcium concentration ([Ca2+]i). However, the role of [Ca2+]i in CDDP induced apoptosis of breast cancer cells (MCF-7) is not well understood. Here we investigate the cytotoxic effects of CDDP in relation to [Ca2+]i homeostasis in MCF-7-sen-sitive and -resistant cell lines. Live-cell imaging using [Ca2+]i sensitive fluorescent dyes was employed to monitor [Ca2+]i CDDP treated MCF-7 cells (0.001-10 μM) and [Ca2+]i modulators i.e. Caffeine (10 mM); Nimodipine (10 μM); Ionomycin (10 μM); Thapsigargin (500 nM). A concentration-dependent increase of [Ca2+]i was observed in CDDP MCF-7 treated cells. From the concentration range tested 100 nM CDDP triggered the highest [Ca2+]i increase (120{\%}; n = 19) while in drug resistant MCF-7 cells the effects of CDDP on [Ca2+]i were reduced as compared with the drug sensitive MCF-7 cells. Furthermore, the CDDP induced cell death correlates with the increase of [Ca2+]i, and thus, significantly lower in the CDDP desensitized cells (p < 0.05). Pre-application of the calcium channel blocker, Nimodipine reduced [Ca2+]i elevation significantly (46.6{\%} increase; n = 26) as well as when a pre-application of Caffeine, Ionomycin or Thapsigargin occurred followed by the subsequent application of CDDP (n = 15; 37.8{\%}, n = 32; 34.9{\%}, n = 21; 53.7{\%} increase respectively).",
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AU - Florea, Ana Maria

AU - Busselberg, Dietrich

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