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Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth.
Oncol Rep. 2006 Jan; 15(1):107-12.OR

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 microM and 50 microM thioridazine-treated, respectively). Apoptosis was confirmed by co-staining of thioridazine-treated B16 cells (12.5 microM) 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 microM and 50 microM). 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.

Authors+Show Affiliations

Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Rabin Medical Center - Beilinson Campus, Petah-Tiqva, Israel. iritgil@post.tau.ac.ilNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16328041

Citation

Gil-Ad, Irit, et al. "Phenothiazines Induce Apoptosis in a B16 Mouse Melanoma Cell Line and Attenuate in Vivo Melanoma Tumor Growth." Oncology Reports, vol. 15, no. 1, 2006, pp. 107-12.
Gil-Ad I, Shtaif B, Levkovitz Y, et al. Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth. Oncol Rep. 2006;15(1):107-12.
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(1), 107-12.
Gil-Ad I, et al. Phenothiazines Induce Apoptosis in a B16 Mouse Melanoma Cell Line and Attenuate in Vivo Melanoma Tumor Growth. Oncol Rep. 2006;15(1):107-12. PubMed PMID: 16328041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth. AU - Gil-Ad,Irit, AU - Shtaif,Biana, AU - Levkovitz,Yechiel, AU - Nordenberg,Jardena, AU - Taler,Michal, AU - Korov,Inna, AU - Weizman,Abraham, PY - 2005/12/6/pubmed PY - 2006/3/11/medline PY - 2005/12/6/entrez SP - 107 EP - 12 JF - Oncology reports JO - Oncol Rep VL - 15 IS - 1 N2 - 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 microM and 50 microM thioridazine-treated, respectively). Apoptosis was confirmed by co-staining of thioridazine-treated B16 cells (12.5 microM) 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 microM and 50 microM). 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. SN - 1021-335X UR - https://www.unboundmedicine.com/medline/citation/16328041/Phenothiazines_induce_apoptosis_in_a_B16_mouse_melanoma_cell_line_and_attenuate_in_vivo_melanoma_tumor_growth_ L2 - http://www.spandidos-publications.com/or/15/1/107 DB - PRIME DP - Unbound Medicine ER -