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Paclitaxel Promotes Oxidative Stress–Mediated Human Laryngeal Squamous Tumor Cell Death through the Stimulation of Calcium and Zinc Signaling Pathways: No Synergic Action of Melatonin

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Abstract

The paclitaxel (PAX) and melatonin (MLT)–mediated mitochondria reactive free oxygen radical (miROS) generations via the influx of excessive Ca2+ and Zn2+ induce tumor cell death and apoptosis. However, a presence of resistance was demonstrated against the PAX treatment in the tumor cells. The stimulation of TRPM2 may increase the anticancer action of PAX after the treatment of MLT. We investigated the stimulating role of PAX with/without MLT on the excessive Ca2+ influx and miROS generation–mediated human laryngeal squamous cancer (Hep2) cell death through the stimulation of TRPM2. The Hep2 cells were divided into four groups as control, MLT (1 mM for 2 h), PAX (50 μM for 24 h), and PAX + MLT. In some experiments, we induced additional subgroups such as PAX+ACA and PAX+2APB. The stimulation of TRPM2 induced the increase of TRPM2 current densities, lipid peroxidation, cytosolic ROS, miROS, cytosolic Ca2+, and Zn2+ values in the Hep2 cells after the treatment of PAX, although their values were decreased by the treatment of MLT and TRPM2 antagonists (ACA and 2APB). In addition, the PAX induced apoptosis and cell death via upregulation of caspases and downregulation of antioxidant glutathione peroxidase and glutathione in the cells. The treatment of PAX increased protein band expression values of TRPM2, PARP-1, and caspase 3 and 9 in the Hep2. The increased expression, apoptotic, and cell death values were not affected by the treatment of MLT. In conclusion, PAX induced the increase of Hep2 cell death via upregulations of TRPM2 and Zn2+, although its downregulation via the treatment of MLT did not change the antitumor action of PAX.

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Funding

The present study was financially supported by the BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture, Industry and Trade Limited Company, Isparta, Turkey. (The number of the project is 2021–02. The owner of the project is Dr. YÇ Kumbul.)

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Authors and Affiliations

  1. Department of Otorhinolaryngology, Faculty of Medicine, Suleyman Demirel University, TR-32260, Isparta, Turkey

    Yusuf Çağdaş Kumbul

  2. Department of Biophysics, Faculty of Medicine, Suleyman Demirel University, TR-32260, Isparta, Turkey

    Mustafa Nazıroğlu

  3. BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture, Industry and Trade Limited Company, Göller Bölgesi Teknokenti, TR-32260, Isparta, Turkey

    Mustafa Nazıroğlu

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  1. Yusuf Çağdaş Kumbul
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Contributions

Dr. M Nazıroğlu and Dr. YÇ Kumbul formulated the present hypothesis and the main manuscript text. The cell culture, antioxidant, and cell viability analyses in the current study were performed in the 5th International Brain Research School, 16 and 22 November 2020, Isparta, Turkey, by Dr. YÇ Kumbul. (http://2020.brs.org.tr/). The remaining analyses were performed by Dr. M Nazıroğlu.

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Correspondence to Mustafa Nazıroğlu.

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Kumbul, Y.Ç., Nazıroğlu, M. Paclitaxel Promotes Oxidative Stress–Mediated Human Laryngeal Squamous Tumor Cell Death through the Stimulation of Calcium and Zinc Signaling Pathways: No Synergic Action of Melatonin. Biol Trace Elem Res 200, 2084–2098 (2022). https://doi.org/10.1007/s12011-022-03125-6

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