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 Table of Contents  
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 60-65

Scutellarein apoptosis mediated by mitochondria in oral squamous cell carcinomas

1 Sri Sairam Siddha Medical College and Research Centre, Chennai, Tamilnadu, India
2 Sri Siddha Medical Center, Chennai 600 091, Tamilnadu, India

Date of Submission30-Sep-2021
Date of Acceptance13-Nov-2021
Date of Web Publication11-Mar-2022

Correspondence Address:
Markandan Birundadevi
Sri Sairam Siddha Medical College and Research Centre, Saileo Nagar, West Tambaram, Chennai - 600 044, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_251_21

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Background: The growth of several cancers can be inhibited by naturally occurring medicinal plants. A flavone called Scutellarein found in the perennial herb Scutellaria lateriflora does have a wide range of biological functions. Scutellarein was studied to determine whether it could induce apoptosis and cause cytotoxicity. Methods: On oral squamous cell carcinoma KB cell lines, Scutellarein's cytotoxic activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Scutellarein was added to KB cells at concentrations ranging from 25 to 125 g/mL for 24 h. The real-time polymerase chain reaction was also used to investigate apoptotic induction potential in Scutellarein-incubated KB cell lines by analyzing Bcl-2 protein and gene expression. Results: In KB-cell lines treated with scutellarein, cytotoxicity and anticancer effects were observed, as well as inhibit the growth of cancer cells. In comparison to the cells not treated with scutellarein, KB cells that had been exposed to scutellarein displayed reduced Bcl-2 expression. Conclusion: KB cells were treated with scutellarein to induce apoptosis, suggesting its potential as a chemo preventative agent. This activity appears to be mediated through the modulation of Bcl-2, a cytotoxic gene.

Keywords: Apoptosis, Bcl2, caspases, KB cells, oral squamous cell carcinomas, scutellarein

How to cite this article:
Birundadevi M, Sivashankar R, Mathukumar S. Scutellarein apoptosis mediated by mitochondria in oral squamous cell carcinomas. Biomed Biotechnol Res J 2022;6:60-5

How to cite this URL:
Birundadevi M, Sivashankar R, Mathukumar S. Scutellarein apoptosis mediated by mitochondria in oral squamous cell carcinomas. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 Aug 19];6:60-5. Available from: https://www.bmbtrj.org/text.asp?2022/6/1/60/339376

  Introduction Top

A significant proportion of oral cancers are locally invasive they also support a high incidence of dissemination, and they are among the most common types of cancer in the world.[1] It is common clinically for oral squamous cell carcinoma (OSCC) to migrate into the mandible and maxilla.[2] Cancer cells are described as having defective apoptosis (programmed cell death) that results in enhanced growth. It is controlled by several proteins to ensure that the cell cycle proceeds at the exact right time to ensure that it divides only when it needs to.[3] Oncology has been impacted greatly by the increasing interest in apoptosis, or programmable cell death, which has had a major impact on many fields within biology.[4] In addition to affecting our understanding of how cancer develops, the delineation of the discrete apoptotic pathway has also influenced our strategies for prevention and therapy.[5] To maintain normal tissue homeostasis, cellular proliferation and death must be balanced, and any abnormality in one of these processes can cause an abnormal clonal expansion characteristic of all neoplastic diseases.[6]

The universal definition of apoptosis is a highly-regulated process of cell suicide that occurs via a variety of intracellular and extracellular factors. An apoptotic cell is largely induced by one of two pathways; one is the mitochondrial pathway, and the other is the death receptor pathway.[7] By losing the mitochondrial transmembrane potential, the mitochondrial pathway of intrinsic apoptosis is triggered. Apoptosis is induced by caspase-9, which functions sequentially. In response to TRAIL and factor-associated suicide ligand, poly (ADP-ribose) polymerase is activated.[8] In addition, chemotherapeutic agents developed from herbal plants have been shown to cause apoptosis as a mechanism for their anticancer effects.[9]

In the perennial herb, Scutellaria lateriflora, a flavone named Scutellariarein (5, 6, 7, 4′-tetrahydroxyflavone) has a wide range of biological properties.[10] According to the most comprehensive study of the herb's active ingredient, scutellarin (40, 5, 6-trihydroxyflavone-7-glucuronide), scutellarein has higher bioavailability because of its improved solubility.[11] A hydrolyzed form of scutellarin, scutellarein, is absorbed more efficiently than the original scutellarin.[12] Scutellaria barbata extract (the main constituent of the extract) is beneficial against colon cancer cell lines in a previous study.[13],[14]

Aiming to examine whether scutellarein could attenuate OSCC development in vitro, we investigated the potential of this compound. A study has been conducted to investigate the potential apoptotic action of scutellarin on cancer cell lines. Our study was therefore conducted to evaluate which extracts have cytotoxic and apoptotic effects on KB cells derived from OSCCs.

  Methods Top


Scutellarein, acridine orange, ethidium bromide, rhodamine 123 stain, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), and dichlorofluorescein diacetate were obtained from Sigma Aldrich, USA. Eagle's minimum essential (MEM) medium, MEM nonessential amino acid solution (×100), fetal bovine serum (FBS), trypsin-ethylenediaminetetraacetic acid (EDTA), Phosphate buffer saline pH 7.4, trypan blue, and antibiotic solution were procured from Hi-Media Laboratories.

Culturing of KB cells

The cells were grown in 10% FBS, Eagle's Minimum Essential Medium with 1% penicillin-streptomycin solution containing an OSCC (KB) cells obtained from NCCS, Pune. 5% CO2 was added to the culture medium every 48 h as the cells were incubated at 37°C. A trypsin-EDTA solution containing 0.25 percent trypsin was used to perform experiments with subcultured cells at 80% confluency.

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay

After seeding and incubating for 24 h at 37°C, 5% CO2, KB cells were plated into a 96-well plate. Scutellarein was applied in different concentrations to the cells after the incubation period (5, 10, 15, 20, 25, and 30 μg/ml) for 24 h. The cells were subjected to an MTT assay, and the medium was discarded. After adding serum-free culture medium to each well and MTT solution, the cells were incubated at 37°C in the dark for 3 h. The plates were wrapped in foil and shook for 15 min after the 150 μl MTT solution was added to each well after incubation. Three replicates of the OD of the solution at 595 nm were measured using a UV spectrophotometer from Shimadzu and calculated to determine the percentage of viable cells.

Staining with acridine orange/ethidium bromide (AO/EtBr)

Scutellarein induced apoptosis on OSCC KB cells using dual staining, AO/EtBr stain. A 20 and 25 μg solution of Scutellarein was treated with KB cells and incubated at 37°C for 24 h. We then rinsed the cells with phosphate-buffered saline (PBS) and stained them with a mixture of acridine orange and ethidium bromide (1:1). A fluorescent microscope was used to examine stained cells after 30 min of incubation in the dark.

Rhodamine-123 staining

Using rhodamine 123 staining, we compared the permeability of mitochondrial membranes between scutellarein-treated cells and untreated cells. A 20 and 25 μg μM scutellarein was added to 24 well plates containing KB cells. Positive control was achieved using doxorubicin administered to the cells 24 h before incubation. After twice rinsing the cells in PBS and staining the cells with 1 mMol rhodamine 123, the cells were incubated for 30 min. A 15-min incubation in dark was performed. Images of fluorescent cells were captured after viewing the stained cells under a fluorescent microscope.

Reactive oxygen species staining

Our cell culture system used 24 well plates to create DCFH-DA staining. A 24 h incubation at 37°C in 5% CO2 followed by treatment with 20 and 25 μg scutellarein was performed on the cells. Staining with 10 μm DCFH-DA stain was performed 30 min after the incubation period. After washing twice with PBS, the cells were examined under an overhead microscope (Olympus) in search of the fluorescent emitters.

Apoptotic staining with propidium iodide

Scutellarein was verified to have an apoptotic effect by morphological detection of DNA stained with propidium iodide (PI). The Scutellarein 20 and 25 g doses were added to the 6-well plates incubated with KB cells for 24 h, with or without Scutellarein treatment. Cells were removed from the compounds, rinsed with PBS, fixed with 70% ethanol for 30 min at room temperature, rinsed twice with PBS, and stained with PI (5 ug/mL in PBS) for 10 min. At excitation 535 nm/emission 615 nm, fluorescence microscopy (Thermo Scientific, USA) revealed chlorophyll fluorescence.

Assay for cellular adhesion

To determine the cell adhesion characteristic feature of KB cells treated with 20 and 25 μg Scutellarein, cell adhesion assays were performed. After seeding cells in serum-free DMEM medium on coated plates, the cells were incubated for 2 h. The cells were rinsed three times with PBS using PBS after 2 h to remove unattached cells. Methanol fixation was applied for 10 min to the remaining adherent cells. The fixed cells were stained for 15 min with methylene blue dye and a microscope was then used to observe and evaluate the cells.

Bcl-2 and caspase-3 gene expression by reverse transcription polymerase chain reaction

The determination of caspase 9 and bcl2 in KB cells treated with 20 and 25 μg was performed by colorimetric-based bcl2 and 9 assay kits (Caspase-9 Colorimetric Protease Assay Sampler Kit and BCL-2 Human enzyme-linked immunosorbent assay Kit, Thermo Fischer Scientific, USA). The test was performed according to the manufacturer's instructions. Analyzing this product with microplates at 450 nm allowed the optical density to be determined. Based on the standard curve graphed with subjective OD values, the concentration of each sample was interpolated and the results were expressed as fold change. The experiments were performed in triplicates.

Statistical analysis

GraphPad Software, Inc., version 6.02, USA software was used to analyze the data after three experiments were conducted. We analyzed the data with a one-way analysis of variance, followed by a post hoc Duncan's test, which was considered statistically significant at P = 0.05.

  Results Top

Scutellarein causes cytotoxicity in KB cells

A 24-h cytotoxicity study of KB cells treated with scutellarein at five different concentrations (5, 10, 15, 20, 25, and 30 μg/ml). A dose-dependent decrease in cell viability is observed when scutellarein is administered to KB cells. Treatment with 20 μg of IC50 resulted in 40% viable cells for the treated cells. We utilized 20 μg scutellarein in the further study because a concentration of 25 μg of scutellarein produced 50% of cell death [Figure 1].
Figure 1: Effect of scutellarein on the cell viability of KB cells. KB cell lines from oral squamous carcinoma were treated with scutellarein (5-30 μg) for 24 h. The cells were subjected to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and the values were depicted as ± standard deviation of three individual experiments

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The KB-cell line is apoptotic in response to scutellarein

Scutellarein treated AO/EtBr stained KB cells. Green fluorescence is greater in control cells with intact nuclei, while green fluorescence is greater in Scutellarein-treated cells, indicating early apoptotic cells at 20 μg of scutellarein. We observed an increase in the proportion of orange-fluorescent late apoptotic cells in cells treated with 25 μg of scutellarein [Figure 2].
Figure 2: Effect of scutellarein on the apoptotic cell death in KB cells. KB cell lines of oral squamous carcinoma were treated with scutellarein for 24 h. Acridine orange and ethidium bromide (1:1), was used to stain the cells and representative stained cells from each group were shown. Control, 20 μg of scutellarein-treated cells and 25 μg of scutellarein-treated cells

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The mitochondrial membrane permeability in KB cells is impaired by scutellarein

Apoptosis was believed to be triggered by an increase in mitochondrial membrane permeability. Hence, we performed rhodamine 123 staining on treated and untreated cells to examine the mitochondrial membrane permeability. 20 μg of scutellarein-treated cells have fewer fluorescent cells (B) in comparison with 25 μg of scutellarein. Control cells showed greater fluorescence [Figure 3].
Figure 3: Effect of scutellarein on the mitochondrial membrane potential in the KB cells. Scutellarein was used to treat oral squamous carcinoma KB cell lines. Rhodamine 123 was used to stain the cells and a representative stained cell was shown for each group. Control, 20 μg of scutellarein-treated cells and 25 μg of scutellarein-treated cells

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Scutellarein induces reactive oxygen species generation in KB cell line

A DCFH-DA staining of KB cells was used to evaluate the reactive oxygen species (ROS) generated by scutellarein. In the control samples, fewer fluorescent cells were observed while the 20 μg of scutellarein and 25 μg of scutellarein treated samples showed more fluorescent cells [Figure 4].
Figure 4: Effect of scutellarein on the intracellular reactive oxygen species production in the KB cells. Scutellarein was used to treat oral squamous carcinoma KB cell lines. A representative stained cell for each group was shown against the cells subjected to DCFH-DA staining. Control, 20 μg of Scutellarein-treated cells and 25 μg of Scutellarein-treated cells

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Scutellarein induces apoptosis in KB cell line

Cytoplasmic and nuclear shrinkage, as well as chromatin condensation, were observed in apoptotic cells. We treated six-well plates with Scutellarein before seeding KB cells in oral cancer. The presence of fluorescently labeled condensed intact nuclei, apoptotic bodies, and a reduction in the number of cells showed that Scutellarein induces apoptosis in PI-stained KB cells. Control cells, however, did not show these changes [Figure 5].
Figure 5: Effect of scutellarein on the apoptotic cell death in the KB cells. KB cell lines of oral squamous carcinoma were treated with scutellarein for 24 h. PI was used to stain the cells and representative stained cells from each group were shown. Control, 20 μg of scutellarein-treated cells and 25 μg of scutellarein-treated cells

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KB cells are ineffective at adhesion when scutellarein is added

Using KB cells treated with doxorubicin and scutellarein for gel cell adhesion assays. Compared to cells treated with doxorubicin and scutellarein, the untreated control group showed an increase in adherent cells. 20 μg of scutellarein treatment decreased the number of adherent cells equally with 25 μg of scutellarein [Figure 6].
Figure 6: Effect of scutellarein on the cell adhesion of KB cells. Scutellarein was used to treat oral squamous carcinoma KB cell lines. In the following figures, representative stained cells of the control and treated groups were shown in cell adhesion assays. Control, 20 μg of scutellarein-treated cells and 25 μg of scutellarein-treated cells

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Scutellarein increases caspase activity in KB cells

We aimed to assess the expression levels of Bcl2 and caspase-9 in scutellarein-treated KB cells that undergo apoptosis. There is a significant increase in Bcl2 and caspase-9 activity in scutellarein-treated cells over control cells. Expression levels of Bcl2 and caspase-9 are based on a dose-dependent manner in LB cells [Figure 7].
Figure 7: Effect of scutellarein on the Bcl-2 and caspase-9 activity in the KB cells. KB cell lines of oral squamous carcinoma were treated with Scutellarein for 24 h. An assay kit based on colorimetry was used to measure bcl2 and 9 activity in cell lysates. The values were depicted as ± standard deviation of three individual experiments. Control, 20 μg of scutellarein-treated cells and 25 μg of scutellarein-treated cells. The data were presented as folds change compared to the untreated “Control” cells and mean ± standard deviation. n = 3, *P < 0.005 compared to the “Control” group

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  Discussion Top

Phytochemicals have been shown by scientists to have antioxidant, antiallergic, anti-inflammatory, antiviral, and antineoplastic properties. It is among the most common types of cancer in India, and low-income populations are especially at risk due to their extensive exposure to health risks.[15] Indians with continuous use of tobacco are known to develop oral cavity tumors. This occurs whether the tobacco is in the form of gutka, zarda, mawa, khaarra, hookah, cigarettes, and bidi.[16] The second-highest cause of death worldwide is cancer, considered to be a huge threat to the global population. By the year 2050, oral cancer will be the number one cancer in India, accounting for approximately 48% of all cancer deaths, with a death rate of 20.5 million per year.[17],[18] Scutellarein effectively up-regulated the expression of mitochondrial Bax and caspase-3 and down-regulated the expression of Bcl-2. Activating mitochondrial signaling pathways by Scutellarein induces apoptosis in SAS human tongue cancer cells.[19] Sun et al.[20] identified a novel therapeutic strategy using combined cisplatin and scutellarin in patients with NSCLC that reverses cisplatin resistance through apoptosis and autophagy. A variety of cancer cell lines are sensitive to flavonoids including scutellarein, pectolinarigenin, and naringin.[21] Matrix metalloproteinase (MMP)-2,-9, and-14 enzymes are inhibited by scutellarein. As a consequence, MMP activation and cell survival were suppressed when scutellarein-mediated nuclear factor-light-chain-enhancer of activated B cells (NF-B) activity was downregulated. The results of this study suggest that scutellarein hinders fibrosarcoma development and inhibits cancer cell metastatic growth.[22] It decreased the activity of P13K/AKT/mTOR signaling, phosphorylated phosphatase, and tensin homolog (PTEN), and increased PTEN levels. When PTEN is overexpressed on RCC cells, it enhances the inhibitory effect of Scutellarein while knockdown of PTEN abrogates it by regulating P13K/AKT/mTOR signaling.[23] In HepG2 cells, scutellarein induces apoptosis by downregulating procaspase-3 and inhibiting the expression of survivin, c-IAP1, HSP27, HSP60, HSP70, HO-1/HMOX1/HSP32, and HO-2/HMOX2.[24] On Jurkat and HCT-116 cell lines,[25] the scutellarein's long aliphatic chain made its antiproliferative effects stronger than that of NaAsO2, the positive control. Yang et al.[26] compared SCU-CD conjugates with scutellarein on human colon cancer cell lines HT-29, SW480, Lovo, and HTC116 and found that the conjugates had better antitumor activity. Several studies have shown that Scutellaerin increases Namalwa cell apoptosis at concentrations of as high as 25 μg, which may be related to caspase activation. Scutellarein appears to be a new potential treatment for lymphoma.[27]

Cancer growth is both promoted and inhibited by ROS. Cancer cells proliferate, invade, and grow through ROS-dependent signaling pathways.[28] Moreover, it causes oxidative stress and impairs the signaling pathway responsible for tumorigenesis.[29] In this study, Scutellarin induces the increased ROS levels that trigger oxidative stress in cancer cells, which then leads to cancer cell death by cytotoxic effect [Figure 1] and [Figure 4]. To effectively treat cancer, it is possible to increase the levels of ROS and reduce the production of antioxidants in the cancer cells. Scutellarein's main biological targets have been suggested to be ROS-mediated cell death and ROS-metabolic enzymes.[30] Many phytocompounds and analogs can bind to several ROS-metabolic enzymes such as NAD (P) H dehydrogenase, quinone 1, carbonyl reductase, glutathione-S-transferase, glyoxalase, and thioredoxin reductase 1 inactivating the enzymes and causing ROS accumulation.[31]

Inhibiting the progression of cancer cells with apoptosis is an effective strategy.[32],[33],[34] An effective inhibitor of cancer cells is a drug targeting apoptotic proteins.[35] Scutellarein was therefore examined for its apoptotic properties against KB cells. Mitochondria are important for the induction of apoptosis since they maintain ATP production, respectively the membrane potential of mitochondrial membranes that control the release of apoptogenic factors into the cytosol. Our Rhodamine 123 staining results show that Scutellarein impaired the mitochondrial membrane in KB. AO/EtBr staining showed high numbers of apoptotic cells, which confirms the fact that Scutellarein changed the membrane potential of mitochondria, causing them to undergo apoptosis [Figure 2] and [Figure 3]. The PI indicator dye cannot cross cell membranes due to its positive charge. It enters the cells and binds to the nuclear DNA when the plasmalemma is damaged and unable to maintain its membrane potential difference.[36] In this study, Apoptosis cells are identified with the help of PI, which is used to determine the integrity of the plasma and nuclear membranes [Figure 5].

Apoptosis is regulated by catalases, which cleave target proteins by converting them into cysteine proteases.[37] Apoptosis is initiated by caspases, both intrinsic and extrinsic.[38] After Scutellarein treatment, leads the expression of Bcl2 and caspase 9 levels increased and cause apoptosis in KB cells. Mitochondrial mediated extrinsic pathway [Figure 7]. This study shows that scutellarein induces apoptosis through caspases. Based on the decrease in adhered cancer cells after treatment of application, these extracts can provide antiproliferative molecules that can target OSCC cells. An adhesion test was conducted to assess the action of Scutellarein on KB cancer cells concerning their metastatic potential.

We examined whether cells' adhesion was compromised by seeding KB cells on adherent cells after treatment [Figure 6]. A statistically significant difference is observed between the Scutellarein-treated cells and the control cells, reduction in adherent cells. It is the first study to demonstrate that extracts play a significant role in developing and advancing OSCC cells. The transcription factor is involved in regulating cytokine expression in cancer cells. Apoptosis, proliferation, and inflammation are other functions of this enzyme. The caspases overexpressed in various cancer cells and Scutellarein reduced pro-inflammatory factors have been reported. The oral epidermal carcinoma KB-cell line was also inhibited and self-destructed by Scutellarein, as demonstrated in studies involving cell adhesion.

  Conclusion Top

Human epidermal cancer cells KB caused by phytoestrogens were found to be inhibited by scutellarein effectively. Reactive oxygen species synthesis and mitochondrial membrane permeability were inhibited by it. Cell proliferation and pro-inflammatory responses were both reduced by the cytotoxic action of Scutellarein. In its role as an anticancer agent, scutellarein can provide an alternative to current allopathic medicines. This study supports this hypothesis, and future investigations on the topic may be useful to develop effective anticancer treatments for OSCC in the future.

Limitation of study

No limitation in the study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]


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