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Research Article
 

Possible Synergistic Effect of Tempol on SCC Treatment and Surgery: An in vitro Study



Cengiz Eser and Halil Mahir Kaplan
 
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ABSTRACT

Background and Objective: Skin and mucosal Squamous Cell Carcinomas (SCCs) are malignant tumours that grow rapidly and cause tissue destruction. Especially, in oral perioral region SCCs where aesthetic and functional repair is required, keeping the excision minimally facilitates the reconstruction. Neoadjuvant or adjuvant therapy with antineoplastic such as cisplatin is of great importance in reducing excision or preventing late-term recurrence in SCCs. TPL induces apoptosis of various tumour cells and has the potential to reduce the side effects of chemotherapeutics. This study aimed to investigate whether tempol will have a synergistic effect with cisplatin, which is used as a traditional chemotherapeutic agent. Materials and Methods: A431 cells (5×104 cells cm–2) were exposed to 2-8 mM TPL and 10-80 μM CIS for 48 hrs. The expression and activity of cleaved Caspase-3, Bax, Bcl-2, Wee 1, GADD153, GRP78 and AIF proteins were examined by ELISA assay in HT29 cells. Results: The data from the ELISA assay indicated that the activities of proapoptotic proteins Bax, cleaved-Caspase 3, Wee 1, GRP78, GADD153 and AIF in human Co-administration of cisplatin with tempol increased apoptotic proteins and decreased cell viability more than their administration alone. Conclusion: In conclusion, study results have shown that tempol can potentiate the effect of cisplatin, which is used as a chemotherapeutic agent, especially in the treatment of SCC, with its potential to reduce its side effects.

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  How to cite this article:

Cengiz Eser and Halil Mahir Kaplan, 2022. Possible Synergistic Effect of Tempol on SCC Treatment and Surgery: An in vitro Study. International Journal of Pharmacology, 18: 1237-1243.

DOI: 10.3923/ijp.2022.1237.1243

URL: https://scialert.net/abstract/?doi=ijp.2022.1237.1243
 
Copyright: © 2022. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

INTRODUCTION

Skin and mucous squamous cell carcinomas are lesions that occur especially in sun-exposed areas as well as genetic predisposition, can grow rapidly and cause serious tissue destruction and death1. Reconstruction can be very difficult, especially in advanced tumours2,3. Reconstruction is more difficult, especially in areas where aesthetic and functional repair must be together, such as the oral region. Neoadjuvant chemotherapy or super-selective chemotherapeutic drug administration methods can also be used in these regions to facilitate4,5. Cisplatin, one of the chemotherapeutic agents, is frequently used, but its side effects cannot be ignored6. Many additional pharmacological agents are used to reduce the side effects and potentiate the effects of chemotherapeutic drugs such as cisplatin, which can be used for functional and aesthetic gain, especially for oral and lip cancers7-9. Tempol (TPL) is a small-molecule nitrogen oxide free radical that can gain or lose electrons via nitroxyl groups to do oxidation or reduction10. TPL induces apoptosis of various tumour cells via pre-oxidation in in vitro cytological assays10,11. However, when the concentration of TPL is low and the treatment time is short, its effect decreases and several animal experiments have shown that TPL can mimic the activity of superoxide dismutase and has antioxidant properties10. TPL is used in the prevention and treatment of oxidative damage, ionizing radiation, hypertension, nervous system injury, ischemia-reperfusion injury and diabetes12-17. Cisplatin is an antitumour drug widely used in clinical practice for the treatment of various solid tumours. The cytotoxic effect of cisplatin is mainly through its binding to nuclear DNA (nDNA) to cause DNA damage, thereby inhibiting nDNA replication and transcription, ultimately leading to tumour cell apoptosis18,19. In addition, cisplatin acts on mitochondrial DNA (mtDNA) to induce ROS generation. High ROS can lead to disruption of the synthesis of proteins in the electron transport chain18. The increase in ROS induced by cisplatin is not only harmful to tumour cells but is also an important cause of nephrotoxicity, neurotoxicity and ototoxicity18,19. Studies have shown that as a chemoprotective agent, TPL can reduce cisplatin-induced ototoxicity and nephrotoxicity20-26 However, increased ROS is also one of the mechanisms by which cisplatin kills tumour cells27. chemotherapeutic cisplatin. Whether TPL affects the antitumour effect of cisplatin is of great importance. Therefore, this study mainly aimed to investigate the effect of the chemo protectant TPL on the antitumour effect of cisplatin and to determine whether TPL in combination with the cisplatin is suitable for the clinical treatment of tumours.

MATERIALS AND METHODS

This study was carried out in the Department of Pharmacology, Faculty of Medicine, Çukurova University between the dates of 01-03-2021 and 30-12-2021.

Reagents: TPL (Adamas reagent), cisplatin, thiazolyl blue [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide MTT], dimethyl sulfoxide (Sigma-Aldrich, USA), cell culture DMEM , trypsin (Gibco, USA), fetal bovine serum (BI, UT, USA).

Cell culture: Human cSCC cell lines A431 were obtained. Squamous cancer cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 4 mM L-glutamine, 1 mM sodium pyruvate, 4,500 mg L–1 glucose and 1,500 mg L–1 sodium bicarbonate. The cells were incubated at 37°C in a humidified incubator supplying 5% CO2.

Cell viability assay (MTT assay): About 5 mg mL–1 dose of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide, Sigma) was prepared by dissolving MTT in filtered Phosphate-Buffered Saline (PBS). Cells were plated at a density of 104 cells cm–2 in 96-well plates in the final volume of 180 μL of medium and incubated overnight. The cells were then treated with a dose of 2-8 mmol L–1 of TPL and 10-80 μM CIS then observed after 48 hrs. Following the treatment with TPL and CIS, MTT as added to each well at a 1/10 volume for 3 hrs at 37°C. The supernatants were carefully aspirated, a volume of 100 μL of dimethyl sulfoxide was added to each well and the plates were agitated to dissolve the crystal product. The absorbance of plates was measured at 570 nm.

Protein quantification: Bradford method was employed to quantify the total protein in homogenized tissues28. By using bovine serum albumin (1 μg mL–1), 1, 2, 3, 5, 7, 8 and 10 μg mL–1 standards were prepared. A volume of 10 μL was taken from every sample and distilled water was added to increase the volume up to 100 μL. A volume of 1 mL of Bradford solution was added to standards and samples, vortexed and absorbances at 595 nanometres were measured manually. Protein quantification (μg μL–1) was done according to the standard curve drawn in Prism software.

ELISA (enzyme-linked immunosorbent assay): ELISA test was used to examine the activity of Caspase-3 and expression of Bax, Bcl-2, Wee 1, GADD153, GRP78 and AIF protein.

Statistical analyses: Results were expressed as Means±S.E.M.. and n refers to the number of animals used for each experiment. Differences in results between tissues were tested by Analysis of Variance (ANOVA) corrected for multiple comparisons (Bonferroni corrections). The p<0.05 were considered to be significant.

RESULTS

TPL and CIS inhibit the proliferation of A431 cells: To investigate the effect of TPL and CIS on cell proliferation, the cell viability MTT test was applied following the application of 2-8 mM TPL and 10-80 μM CIS. The cell viabilities of A341 cells were suppressed by TPL (Fig. 1a). and CIS (Fig. 1b). in a dose-dependent manner. The proliferation rate of A341 cells was also inhibited by TPL and CIS at various doses, compared with the control group. 10μM CIS combined with 20 mM TPL treatment increased the proliferation rate of A341 more than a single treatment of these agents (Fig. 1c).

Bcl-2 protein determination: Administration of the CIS+TPL combination to the cells significantly increased the expression of the anti-apoptotic protein Bcl-2 (Fig. 2).

ELISA quantification of Caspase-3: Administration of the CIS+TPL combination to cells significantly increased Caspase-3 (Fig. 3).

ELISA quantification of Bax: Administration of the CIS+TPL combination to the cells significantly increased Bax (Fig. 4).

ELISA quantification of Wee 1: The combination of CIS+TPL increased Wee 1 more than CIS and TPL alone (Table 1).

ELISA quantification of AIF: The combination of CIS+TPL increased AIF more than CIS and TPL alone (Table 1).

ELISA quantification of GADD153: The combination of CIS+TPL increased GADD153 more than CIS and TPL alone (Table 1).

Image for - Possible Synergistic Effect of Tempol on SCC Treatment and Surgery: An in vitro Study
Fig. 1(a-c): Effect of (a) TPL, (b) CIS and (c) Combination on the viability of A341 cells (n = 6)
Statistical analysis: Student t-test, (significant relative to “*: Control” and “#: CIS” p<0.05)


Image for - Possible Synergistic Effect of Tempol on SCC Treatment and Surgery: An in vitro Study
Fig. 2: Effect of CIS+TPL combination on Bcl-2 protein in A341 cells (n = 6)
Statistical analysis: Student t-test, (Significant relative to “*: Control” and “#: CIS” p<0.05)


Image for - Possible Synergistic Effect of Tempol on SCC Treatment and Surgery: An in vitro Study
Fig. 3: Effect of CIS+TPL combination on Caspase-3 protein in A341 cells (n = 6)
Statistical analysis: Student t-test (Significant relative to “*: Control” and “#: CIS” p<0.05)


Image for - Possible Synergistic Effect of Tempol on SCC Treatment and Surgery: An in vitro Study
Fig. 4: Effect of CIS+TPL combination on Bax protein in A341 cells (n = 6)
Statistical analysis: Student t-test. (Significant relative to “*: Control” and “#: CIS” p<0.05)


Table 1: Effects of CIS and TPL on the expression of mitotic division inhibitors
Control (pg mL–1) CIS (pg mL–1) TPL (pg mL–1) CIS+TPL (pg mL–1)
Wee 1 0.25±0.022 0.68±0.015* 0.45±0.01 0.82±0.04#
AIF 0.63±0.05 2.3±0.15* 1.75±0.08 2.9±0.3#
GADD153 0.33±0.02 3.2±0.3* 2.2±0.2 3.9 ±0.2#
GRP78 0.63±0.025 5.2±0.5* 0.43±0.05 7.3±0.8#
Results are presented as Mean±SE, statistical analysis: ANOVA, post hoc: Bonferroni, (significant relative to “*: Control” and “#: CIS” p<0.05)

ELISA quantification of GRP78: The combination of CIS+TPL increased GRP78 more than CIS and TPL alone (Table 1).

DISCUSSION

Definitive excision and repair is a very challenging process, especially in patients with large-sized squamous cell cancer. Reconstruction becomes even more important, especially in oral and perioral region lesions. The reason for this is the necessity of providing oral competence as well as providing an aesthetic appearance in the reconstruction of the defect formed after excision. In this case, it may make sense to reduce the size of the excision. For this purpose, preoperative chemotherapy or adjuvant treatment can be applied in case of possible recurrence4. Cisplatin is one of the main chemotherapeutic agents in cancers29-32. Besides being used as a neoadjuvant or adjuvant, super-selective applications are also made to reduce its side effects5. Another way to reduce side effects is to apply some substances in the form of a combined treatment.

This study demonstrated that TPL has a synergistic anti-tumour effect with cisplatin in cytological experiments. TPL has been shown to increase cisplatin-induced tumour cell apoptosis. TPL is an antioxidant with good membrane permeability and low toxicity. Thanks to its superoxide anion scavenging activity, it can prevent the production of superoxide ions and H2O2 in mitochondria and reduce cellular oxidative damage. The United States is conducting a clinical trial of TPL to reduce the side effects of cisplatin, so the results of this study were a guide and reference source for the trial. The redox properties of TPL have oxidative and reducing properties by gaining or losing electrons via Nitroxyl groups10,33. When shown to be oxidative, TPL can increase the expression of the cell cycle-dependent kinase inhibitor p21waf1/cip1 and activate the functions of the Caspase-3 and Bax/Bcl-2 pathways10. The cytotoxic effect of TPL is due to stimulation of cells and Internal oxidative stress, thereby killing tumour cells10. When reducing, TPL can simulate the action of superoxide dismutase and catalase, scavenge superoxide anion free radicals, reduce protein damage and attenuate the effects of lipid peroxidation on cell membranes11. However, whether TPL is oxidative or reductive is affected by drug concentration, duration of action, medium of drug action and many factors that are difficult to determine7,27. Oxidative stress in tumour cells is one of the mechanisms of the anti-tumour and toxic side effects of cisplatin. Therefore, in vivo experiments, TPL can reduce the toxic and side effects of cisplatin on other organs, as well as reduce the toxicity of cisplatin. In cytological experiments, TPL concentration was constant and the duration of action was long, TPL exerted a pro-oxidative effect, activated the function of Caspase-3 and the Bax/Bcl-2 pathway and synergistically inhibited cell survival with cisplatin10,33.

The nitroxide free radical of TPL has a very short half-life in plasma and a shorter residence time in tumour tissue33. In a study using MRI to detect nitroxide (3-CP) metabolism in normal and tumour tissue in mice, it was observed that nitroxide free radicals (3-CP) reached a maximum at 8.5 min and then began to decrease10. Therefore, when TPL is used alone, a higher dose of TPL is required to achieve a better anti-tumour effect. How to increase the drug concentration and drug effect time of TPL in the blood is an important problem that needs to be solved for TPL to have a better anticancer effect.

Generally speaking, when the drug has a short duration of action and low drug concentration, it is antioxidant, protects cells from oxidative damage and when drug concentration is high and continues to act, it is prooxidative and kills tumour cells10,33. Doses of TPL used in in vivo studies are difficult to achieve high concentrations and sustained action times to kill tumour cells. Therefore, in these in vivo studies, even when the maximum tolerated dose of TPL is reached, TPL still acts only as an antioxidant33.

In this study, it was shown that in vitro tempol potentiates the effects of cisplatin, which is especially used in the treatment of SCC and reduces its side effects. Based on this result, it can be assumed that the tempol+cisplatin combination to be applied will reduce the tumoural mass of the SCC. The specified combination can reduce the defect that will occur in neoadjuvant applications or treatment can be provided in relapsed cases after surgery. Reducing the tumoral mass to be surgically excised means ultimately reducing the defect to be reconstructed. This becomes very important in tumours that require aesthetic and functional reconstruction, especially in the oral region. The main limitation of the study is that the specified combination was administered in vitro.

CONCLUSION

This study suggested that when TPL is used simultaneously as an antioxidant and cisplatin as a chemotherapy drug, the pros and cons should be weighed, the benefits of TPL in reducing the toxic and side effects caused by chemotherapy drugs should be evaluated and the risk of reducing the effects of chemotherapy drugs should be evaluated simultaneously. This study also provides a reference for the use of other antioxidants in combination with cancer chemotherapeutics, particularly through ROS-increasing drugs. Finally, it is suggested that the side-effect-reducing and antitumour properties of tempol can be utilized in adjuvant or neoadjuvant cisplatin applications, especially in body areas where aesthetic and functional repair is required, such as the oral region.

SIGNIFICANCE STATEMENT

This study discovered the anti-cancer effect of TPL in human squamous cell carcinomas cell line A341. This study also revealed the importance of the synergistic effect of TPL in the treatment of human squamous cell carcinomas. Thus, a new theory that TPL has a synergistic effect in the fight against human squamous cell carcinomas together with conventional chemotherapy may be arrived at.

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