Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth

  • Authors:
    • Irit Gil-Ad
    • Biana Shtaif
    • Yechiel Levkovitz
    • Jardena Nordenberg
    • Michal Taler
    • Inna Korov
    • Abraham Weizman
  • View Affiliations

  • Published online on: January 1, 2006     https://doi.org/10.3892/or.15.1.107
  • Pages: 107-112
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Abstract

Phenothiazines and related antipsychotics were reported to have an antiproliferative effect in several tissue cultures. The aims of this study were: a) to screen in vitro, the potential anti-cancer activity of phenothiazines in wild-type and multi-drug resistant (MDR) B16 mouse melanoma cell lines; and b) to determine the in vivo anti-tumor effect of an in vitro selected highly potent phenothiazine (thioridazine) in a murine melanoma model. The following phenothiazines were evaluated: perphenazine, fluphenazine, thioridazine trifluoperazine and chlorpromazine. All agents induced a dose-dependent decrease in cell viability in wild-type and in MDR B16 melanoma cells. Thioridazine displayed the highest antiproliferative activity. Flow cytometric analyses of 24-h treated B16 melanoma cells revealed an increase in fragmented DNA (16.3 vs 71.3% and 87.2% in controls, 25 µM and 50 µM thioridazine-treated, respectively). Apoptosis was confirmed by co-staining of thioridazine-treated B16 cells (12.5 µM) with propidium iodide and Hoechst 33342 reagents. Caspase-3 expression, a typical mediator of apoptosis, was markedly increased following a 4-h exposure of B16 cells to thioridazine (25 µM and 50 µM). This increase could be blocked by a specific caspase-3 inhibitor. In vivo studies were performed using female C57/Bl mice. Animals were inoculated with wild-type B16 cells by i.v. injection into the tail vein. Mice were treated with thioridazine (10 and 15 mg/kg x3/week i.p. or 15, and 25 mg/kg/day p.o.) and control animals received saline. Mice were monitored for 21-30 days. Body weight was recorded. After autopsy, the lung weight and number of pulmonary melanoma colonies were determined. Thioridazine administration (i.p. or p.o.) resulted in the reduction of lung tumor burden and an increase in mice survival. In conclusion, several phenothiazines, and particularly thioridazine, induced apoptosis of B16 melanoma cells and demonstrated in vivo anti-tumor activity.

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January 2006
Volume 15 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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APA
Gil-Ad, I., Shtaif, B., Levkovitz, Y., Nordenberg, J., Taler, M., Korov, I., & Weizman, A. (2006). Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth. Oncology Reports, 15, 107-112. https://doi.org/10.3892/or.15.1.107
MLA
Gil-Ad, I., Shtaif, B., Levkovitz, Y., Nordenberg, J., Taler, M., Korov, I., Weizman, A."Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth". Oncology Reports 15.1 (2006): 107-112.
Chicago
Gil-Ad, I., Shtaif, B., Levkovitz, Y., Nordenberg, J., Taler, M., Korov, I., Weizman, A."Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth". Oncology Reports 15, no. 1 (2006): 107-112. https://doi.org/10.3892/or.15.1.107