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Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells

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Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells ORIGINAL RESEARCH published: 29 July 2021 doi: 10.3389/fphar.2021.673103 Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells Shoaib Shoaib 1, Saba Tufail 1, Mohammad Asif Sherwani 2, Nabiha Yusuf 2 and Najmul Islam 1* 1Department of Biochemistry, J.N.M.C, Aligarh Muslim University, Aligarh, India, 2Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, United States The latest research shows that current chemotherapeutics are ineffective because of the development of resistance in cervical cancer cells, and hence, their scope of use is limited. The main concern of researchers at the moment is the discovery of safe and effective antiproliferative plant chemicals that can aid in the battle against cervical cancer. Previous studies have shown the possible anticancer potential of phenethyl isothiocyanate obtained Edited by: from cruciferous plants for many cancers, which targets various signaling pathways to Farrukh Aqil, exercise chemopreventive and therapeutic effects. This provides the basis for studying University of Louisville, United States phenethyl isothiocyanate’s therapeutic potential against cervical cancer. In the present Reviewed by: study, cervical cancer cells were treated with various doses of phenethyl isothiocyanate, Hamidullah Khan, fi University of Wisconsin–Madison, alone and in combination with cisplatin. Phenethyl isothiocyanate alone was suf cient to United States cause nucleus condensation and fragmentation and induce apoptosis in cervical cancer Irfan Ansari, cells, but evident synergistic effects were observed in combination with cisplatin. In Integral University, India Farrukh Afaq, addition, phenethyl isothiocyanate treatment increased the production of intracellular University of Alabama at Birmingham, ROS in a dose-dependent manner in cervical cancer cells. Furthermore, investigation United States of phenethyl isothiocyanate induced mitochondrial reactive oxygen species production, *Correspondence: fi Najmul Islam and activation of caspases showed that phenethyl isothiocyanate signi cantly activated [email protected] caspase-3. Specialty section: Keywords: cervical cancer, HPV16+, ROS, apoptosis, DNA fragmentation This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal INTRODUCTION Frontiers in Pharmacology Received: 26 February 2021 Being one of the critical and major public health problems, cervical cancer stands fourth in women Accepted: 14 June 2021 and seventh among all the cancers in the world (Ferlay et al., 2015). Epidemiological studies have Published: 29 July 2021 indicated its high incidence and mortality, accounting for 0.57 million cases and 0.311 million deaths Citation: in 2018 (Cohen et al., 2019). In most cervical cancer malignancies, human papilloma virus Shoaib S, Tufail S, Sherwani MA, (HPV) infection was found to be related to HPV16 and HPV18 at higher risk (Moody and Yusuf N and Islam N (2021) Phenethyl Laimins, 2010). Although medical facilities have progressed, cervical cancer is still rising in Isothiocyanate Induces Apoptosis terms of incidence and deaths worldwide due to the lack of cost-effective diagnosis and Through ROS Generation and Caspase-3 Activation in Cervical therapies (Arbyn et al., 2011). Cancer Cells. The most common cervical cancer treatment strategies are hysterectomy, radiotherapy, Front. Pharmacol. 12:673103. chemotherapy, and chemoradiotherapy. The surgery is successful if cervical cancer is diagnosed doi: 10.3389/fphar.2021.673103 early, but largely, metastasized cervical cancer is diagnosed at the late stage (Sak, K., 2014). Radiation Frontiers in Pharmacology | www.frontiersin.org 1 July 2021 | Volume 12 | Article 673103 Shoaib et al. PEITC Induces Apoptosis therapy of patients with cervical cancer or any other cancer has Determination of Cell Viability Using MTT been reported for adverse side effects on the gastrointestinal, Assay gynecological, and urological systems (Klee et al., 2000). The To determine the effect of phenethyl isothiocyanate on normal concurrent use of chemotherapy combined with radiotherapy has human keratinocyte, HaCaT cells and cervical cancer cells (CaSki also been reported to give rise to hematologic and gastrointestinal and HeLa) were analyzed using MTT assay. Briefly, the cells were fi side effects in cervical cancer (Eifel, 2006). The standard rst-line seeded into a 96-well plate at a density of 5 × 103 cells per well in medicaments (chemotherapeutics) for the treatment of cervical triplicate and incubated at 37°C for 24 h. The cells were treated fl – cancer are cisplatin and 5- uorouracil based chemotherapy; with different concentrations of PEITC (0, 2, 5, 10, 15, 20, and however, it is accompanied by drug resistance. Reckoning with 25 µM) for 24 and 48 h. Control group cells were treated with these conditions, the development of a safe treatment plan, which 0.01% DMSO in media. Subsequently, cell survival was is more precise and effective, with the least side effects is urgently determined by adding 10 µL of 5 mg/ml MTT reagent in each required. well, followed by incubation for 4 h at 37°C, and then 100 µL of In recent decades, cervical cancer has been targeted by a dimethyl sulfoxide was added to dissolve formazan by gentle variety of herbal compounds for their anticancer potential, shaking. The absorbance of each well was measured at 570 nm, creating opportunities to discover new anticancer medicines to and cell survival was calculated as percentage over the control. address the problems of drug resistance and adverse side Additionally, cisplatin was also used to determine and compare effects caused by traditional therapies. Multiple herbal cytotoxicity on the cell lines, either alone or in combination with compounds have been shown to have important effects on the tested compound. The purpose of including HaCaT cells various signaling pathways of the cervical cancer cell (normal keratinocyte cell line) is to compare the cytotoxic effect (Chauhan et al., 2009; Moga et al., 2016). Phenethyl of phenethyl isothiocyanate. isothiocyanate (PEITC), most commonly seen in watercress and cruciferous vegetables, exhibits various beneficial behaviors. In cancer cells, PEITC has been Analysis of Morphological Changes by shown to have antioxidant, anti-inflammatory, and Phase Contrast Microscopy antiproliferative activity and induces apoptosis (Xu et al., The morphological changes in PEITC-treated normal and 2005; Satyan et al., 2006; Hong et al., 2015; Sarkar et al., 2016; cervical cancer cells were analyzed by phase contrast Ramirez et al., 2018). In the current study, we tried to microscopy as described previously (Kim et al., 2015). 5 × 103 investigate the effects of PEITC on the HPV16+ and cells were seeded per well in a 96-well plate in triplicate and HPV18+ cervical cancer cell lines (CaSki and HeLa). ° incubated for 24 h in a 5% CO2 incubator at 37 C. Thereafter, the cell lines were re-supplemented with increasing concentrations of PEITC for 24 h, and then cellular morphological changes were MATERIALS AND METHODS observed under a phase contrast microscope and compared with Reagents the control untreated cell group. All the reagents used in this study were of molecular grade. PEITC, cisplatin, propidium iodide (PI), 4,6-diamidino-2-phenylindole Determination of DNA Fragmentation by (DAPI), 2,7-dichlorofluorescein diacetate(DCF-DA), DAPI Staining dihydrorhodamine 123, N-acetylcysteine (NAS), 3-(4,5- The nuclear morphology of the apoptotic cells was observed by dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), fluorescence microscopy after DAPI staining (Al-Otaibi et al., 2018). dimethyl sulfoxide, and caspase-3, -8, and -9 inhibitors were Briefly, 5 × 103/ml CaSki and HeLa cells were seeded into a 6-well procured from Sigma Aldrich Chemical Co. (United States). plate, followed by incubation for 24 h, and then treated with various Caspase activity kits were purchased from BioVision, concentrations of PEITC for 24 h. Thereafter, the cells were washed United States, and an FITC Annexin V Apoptosis kit was with cold phosphate-buffered saline (PBS) and fixed in ice-cold 70% obtained from BD Biosciences (United States). Fetal bovine methanol for 10 min. The cells were then stained with DAPI and ’ fi ’ serum (FBS), Dulbecco smodied Eagle smedium(DMEM), incubated for 15 min at 37°Cinthedark.Finally,thecellswereagain fi and other chemicals were purchased from Thermo Fisher Scienti c. washed with PBS, and the cells were observed under a fluorescence Cell Culture microscope (Nikon ECLIPSE Ti-S, Japan). Human cervical cancer cell lines (CaSki and HeLa) and a normal human keratinocyte cell line (HaCaT) were Determination of Apoptosis by Flow purchased from the National Center for Cell Sciences (NCCS), Pune, India and ATCC, respectively. The cells Cytometry and Annexin-V FITC/Propidium were grown in DMEM supplemented with 10% FBS and Iodide Staining 1% antibiotic–antimycotic solution containing penicillin The prominent characteristic of apoptosis is the alteration in the and streptomycin. The cells were maintained in a distribution of phosphatidylserine on the two leaflets of the plasma fi ° humidi ed atmosphere containing 5% CO2 at 37 Cina membrane. The apoptosis induction was determined using the ’ CO2 incubator. annexin V-FITC kit according to the manufacturer s protocol. In Frontiers in Pharmacology | www.frontiersin.org 2 July 2021 | Volume 12 | Article 673103 Shoaib et al. PEITC Induces Apoptosis FIGURE 1 |
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