Capsaicin-induced genotoxic stress does not promote apoptosis in A549 human lung and DU145 prostate cancer cellsby Anna Lewinska, Paulina Jarosz, Joanna Czech, Iwona Rzeszutek, Anna Bielak-Zmijewska, Wioleta Grabowska, Maciej Wnuk

Mutation Research/Genetic Toxicology and Environmental Mutagenesis

About

Year
2015
DOI
10.1016/j.mrgentox.2015.02.003
Subject
Health, Toxicology and Mutagenesis / Genetics

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Mutation Research 779 (2015) 23–34

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Capsaicin-induced genotoxic stress does not promote apoptosis in

A549 human lung and DU145 prostate cancer cells

Anna Lewinskaa,∗, Paulina Jaroszb, Joanna Czechb, Iwona Rzeszutekb,

Anna Bielak-Zmijewskac, Wioleta Grabowskac, Maciej Wnukb a Department of Biochemistry and Cell Biology, University of Rzeszow, Zelwerowicza 4, 35-601 Rzeszow, Poland b Department of Genetics, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland c Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, PAS, Pasteura 3, 02-093 Warsaw, Poland a r t i c l e i n f o

Article history:

Received 29 November 2014

Received in revised form 8 February 2015

Accepted 10 February 2015

Available online 16 February 2015

Keywords:

Capsaicin

Cancer cells

DNA damage

Micronuclei

Oxidative stress

DNA methylation a b s t r a c t

Capsaicin is the major pungent component of the hot chili peppers of the genus Capsicum, which are consumed worldwide as a food additive. More recently, the selective action of capsaicin against cancer cells has been reported. Capsaicin was found to induce apoptosis and inhibit proliferation of a wide range of cancer cells in vitro, whereas being inactive against normal cells. As data on capsaicin-induced genotoxicity are limited and the effects of capsaicin against human lung A549 and DU145 prostate cancer cells were not explored in detail, we were interested in determining whether capsaicin-associated genotoxicity may also provoke A549 and DU145 cell death. Capsaicin-induced decrease in metabolic activity and cell proliferation, and changes in the cell cycle were limited to high concentrations used (≥100M), whereas, at lower concentrations, capsaicin stimulated both DNA double strand breaks and micronuclei production. Capsaicin was unable to provoke apoptotic cell death when used up to 250M concentrations. Capsaicin induced oxidative stress, butwas ineffective in provoking the dissipation of the mitochondrial inner transmembrane potential. A different magnitude of p53 binding protein 1 (53BP1) recruitment contributed to diverse capsaicin-induced genotoxic effects in DU145 and A549 cells. Capsaicin was also found to be a DNA hypermethylating agent in A549 cells. In summary, we have shown that genotoxic effects of capsaicin may contribute to limited susceptibility of DU145 and A549 cancer cells to apoptosis in vitro, which may question the usefulness of capsaicin-based anticancer therapy, at least in a case of lung and prostate cancer. © 2015 Elsevier B.V. All rights reserved. 1. Introduction

Capsaicin, a homovanillic acid derivate (8-methyl-N-vanillyl-6nonenamide), is the most abundant pungent ingredient found in pepper plants (genus Capsicum, family Solanaceae) that is widely used as a spice [1]. Capsaicin has been previously used to treat pain and inflammation associated with neuropathic pain conditions, such as rheumatoid arthritis, cluster headaches, herpes zoster and vasomotor rhinitis [2–5]. More recently, anticancer activity of capsaicin has been demonstrated [6]. Capsaicin-mediated apoptosis and/or antiproliferative potential has been reported for numerous cancer cell lines, e.g., in leukemia cells [7], multiple myeloma cells [8], cutaneous cell carcinoma [9], glioma cells [10], tongue cancer cells [11], nasopharyngeal carcinoma cells [12], esophageal ∗ Corresponding author. Tel.: +48 17 785 54 03; fax: +48 17 872 12 65.

E-mail address: alewinska@o2.pl (A. Lewinska). carcinoma cells [13], gastric cancer cells [14], pancreatic cancer cells [15], hepatocarcinoma cells [16], colon carcinoma cells [17], small cell lung cancer [18], breast cancer cells [19] and prostate cancer cells [20]. It is widely accepted that capsaicin-associated anticancer effects may be executed by reactive oxygen species (ROS) production, cell cycle arrest, regulation of transcription factor expression and changes in growth/survival signal transduction pathways, such as EGFR/HER-2 pathway or NF-B inactivation [9,15,19,21–24]. In contrast, capsaicin-induced autophagy may result in the suppression of endoplasmic reticulum (ER) stressmediated apoptosis, which, in turn, may cause an attenuation of cancer cell death response, e.g., in malignant breast cells [25].

Because capsaicin carcinogenic and tumorigenic properties have also been suggested [26], the mechanisms underlying capsaicin cytotoxicity and chemotherapeutic activity require clarification.

It has been postulated and rebutted that capsaicin may stimulate genotoxic effects [27–30]. These discrepancies may rely on different protocols and diverse biologicalmaterials used to address http://dx.doi.org/10.1016/j.mrgentox.2015.02.003 1383-5718/© 2015 Elsevier B.V. All rights reserved. 24 A. Lewinska et al. / Mutation Research 779 (2015) 23–34 capsaicin-induced genotoxicity [27–30]. Of course, in a case of anticancer therapy itwouldbebeneficial if capsaicin-inducedexcessive

DNA damage would provoke apoptotic cell death and cancer cell elimination.

In the present study, a link between capsaicin-induced genotoxicity and cytotoxicity has been evaluated. To address capsaicin genotoxic potential, we used two distinct cancer cell lines, namely,

A549 lung adenocarcinoma and DU145 prostate adenocarcinoma cells, because data on capsaicin-induced cytotoxicity and genotoxicity against these cancer cells are limited and lacking, respectively. Surprisingly, capsaicin-associated genotoxic effects were not accompanied by apoptosis, which may have implications for capsaicin-based anticancer therapy. 2. Materials and methods 2.1. Reagents

Capsaicin (12084, analytical standard grade, ≥99%) was purchased from Sigma (Poznan, Poland), phosphate-buffered saline (PBS) was obtained from Gibco, Invitrogen Corporation (Grand