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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 65  |  Issue : 3  |  Page : 136-142

A synthetic biscoumarin suppresses lung cancer cell proliferation and induces cell apoptosis by increasing expression of RIP1


1 School of Medicine, Foshan University, Foshan, Guangdong, China
2 Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, China
3 School of Medicine, Foshan University; R&D Department, Foshan Newtopcome Pharmaceutical Technology Co., Ltd., Foshan, Guangdong, China

Date of Submission15-Dec-2021
Date of Decision13-Apr-2022
Date of Acceptance20-Apr-2022
Date of Web Publication27-Jun-2022

Correspondence Address:
Dr. Zhaoguang Zheng
School of Medicine, Foshan University, 5 Hebin Road, Chancheng Area, Foshan; R&D Department, Foshan Newtopcome Pharmaceutical Technology Co., Ltd., No. 129 West Jihua Road, Chancheng Area, Foshan, Guangdong
China
Prof. Zhengquan Su
Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, 280 Waihuan East Road, Guangzhou
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjp.cjp_107_21

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  Abstract 


Coumarin has a variety of biological activities and widely exists in plants. Biscoumarin, derived from coumarin, their synthetic methods and bioactivities of biscoumarins is the hotspot of the current research. In this study, we evaluated for the first time the anticancer of a synthetic biscoumarin (3,3'-(4-chlorophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one, C3) on lung cancer cells and explored the related mechanism. C3 was simply prepared by 4-hydroxycoumarin and 4-chlorobenzaldehyde under ethanol. The structure of C3 was elucidated by various spectroscopic analyses. The antiproliferation effect of C3 was evaluated by the cell counting kit-8 assay. Cell cycle and apoptosis analysis were detected by flow cytometry. The expression of correlated proteins was determined using Western blotting. The result showed that C3 displayed a strong cytostatic effect on Lewis lung cancer (LLC) cells. C3 inhibited the proliferation of LLC cells, and induced G2/M phase cell cycle arrest. In addition, C3 possessed a significant reduction on cell apoptosis by increasing of RIP1 expression. Our data showed that C3 suppresses lung cancer cell proliferation and induces cell apoptosis, which is possibly involved with the RIP1.

Keywords: Apoptosis, biscoumarin, lung cancer, proliferation, RIP1


How to cite this article:
Wang R, Xie H, Wang X, Liu Y, Su Z, Zheng Z. A synthetic biscoumarin suppresses lung cancer cell proliferation and induces cell apoptosis by increasing expression of RIP1. Chin J Physiol 2022;65:136-42

How to cite this URL:
Wang R, Xie H, Wang X, Liu Y, Su Z, Zheng Z. A synthetic biscoumarin suppresses lung cancer cell proliferation and induces cell apoptosis by increasing expression of RIP1. Chin J Physiol [serial online] 2022 [cited 2022 Aug 10];65:136-42. Available from: https://www.cjphysiology.org/text.asp?2022/65/3/136/348358

Ruixue Wang and Hongyi Xie contributed equally to this article.





  Introduction Top


Lung cancer is the leading cause of cancer-related mortality, with non-small-cell lung cancer (NSCLC) as the most prevalent form with a poor 5-year survival of 18%. Despite advances in treatment options, including surgery, radiation, chemotherapy, and targeted therapies, prognosis remains poor. In recent years, immunotherapy has been supposed to be an attractive treatment investigated in lung cancer. Despite prolonged overall survival, only a minority of the lung carcinoma patients derive clinical benefits from these treatments. Hence, alternative therapeutics need to be developed for the better treatment of lung cancer.

Both natural and synthetic coumarin-based compounds have multiple functions, such as anti-inflammatory,[1],[2] antibacterial,[3],[4],[5] antiviral,[6] inhibition of cyclooxygenases,[7],[8] antioxidant,[9],[10] antithrombotic,[11] inhibition of lipoxygenase,[8],[12] inhibition of xanthine oxidase,[13] and anti-Alzheimer's Disease.[14],[15] In recent years, more and more researches are focused on the anticancer activities and its mechanisms. Coumarin derivatives, such as furocoumarins, pyranocoumarins, and biscoumarins, have been identified through different mechanisms of action, such as alkylating agents, topoisomerase inhibitors, hormone antagonists, angiogenesis inhibitors, antimitotic agents, apoptosis inducers, human carbonic anhydrase inhibitors, telomerase inhibitors, and other drugs.[13] Biscoumarins are conventionally used as anticoagulant, represented by warfarin, dicoumarin, and ethyl biscoumacetate. In recent years, anticancer activities are also reported. New series of naphthoquinone-coumarin conjugates were developed and examined as topoisomerase inhibitors by Hueso-Falcón et al.[16] in 2017. Reddy et al.[17] synthesized a series of new C4-C4' biscoumarin-pyrimidine conjugates and evaluated the anticancer activity against C6 rat glioma cells.

Many natural and synthetic coumarins have been comprehensively studied in structure, nontoxicity, and biological characteristics. In this study, we synthesized a biscoumarin and evaluated for the first time the anti-cancer effect on lung cancer cells, and explored the related mechanism.


  Materials and Methods Top


Chemicals and apparatus

The established line of A549, H460, and Lewis lung cancer (LLC) cells were obtained from The Chinese Center for Type Culture Collection. Cell counting kit (CCK-8) test kit was purchased from Dojindo, Japan. Fetal calf serum was obtained from Sijiqing Serum Factory of Hangzhou City. Tips, dishes, test tubes, etc., for cell culture were bought from Thermo Fisher Scientific (Waltham, MA, USA).

Nuclear magnetic resonance (NMR) data were collected on a Bruker AM-400 spectrometer in DMSO-d6 (Bruker, Fällanden, Switzerland). High resolution electrospray ionization mass spectrometry (HR-ESI-MS) were performed in MeOH on a thermofisher LCQ-Fleet spectrometer (Thermo Fisher Scientific, San Jose, CA, USA). The melting point was detected by RY-2 melting point meter (Tianjin Analytical Instrument Factory, Tianjin, China).

Sythesis of compound 3 (C3)

Sythesis of C3 is according to the literature.[18] In detail, 1.62 g (10 mmol) 4-hydroxycoumarin (1) and 5 mmol 4-Chlorobenzaldehyde (2) were dissolved in 20 mL ethanol, placed in a 50 ml round-bottom flask, stirred and heated at reflux for 4 h, solid precipitation could be seen in the reaction, monitored by TLC until the end of the reaction, cooled and filtered, the precipitate was recrystallized with ethanol to obtain 3 [C3, [Figure 1]].
Figure 1: Synthesis of C3.

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In vitro anti-tumor activities

NSCLC cells (A549, H460, LLC) and the rat cardiomyocytes H9C2 cells were seeded in 96-well plates (2000/well). Then, C3 were diluted to different concentrations and added into wells (3 wells per concentration) for 72-h incubation. CCK-8 test was performed according to the protocol. In brief, CCK-8 solutions were added to each well and maintained at 37°C for 1 h. Then, the OD values were measured at 450 nm using a microplate reader (Bio-Rad, Hercules, CA, USA). The inhibition of cell proliferation was calculated by the following formula: inhibition (%) = (Ac − At)/Ac×100 where Ac is the absorbance of the control group and At is the absorbance of C3-treated group.

Cell cycle analysis

LLC Cells were seeded in 6-well plates (5 × 104 cells/well), followed by starved in serum-free medium for 12 h. After replacing the serum-free medium with a complete Dulbecco's Modified Eagle Medium (DMEM) containing C3 or phosphate-buffered saline (PBS), the cells were cultured for 48 h, then the cells were harvested and resuspended in PI solutions according to the instructions. After incubation for 30 min in the dark at 37°C, the treated cells were analyzed by flow cytometry (CytoFLEX S, Beckman, USA). The percentages of G0/G1, S, and G2/M stage cells were quantified using CytExpert software (Beckman Coulter, IN, USA).

Western blot analysis

LLC cells were seeded in 12-well plates (1 × 105 cells/well), followed by culture in serum-free DMEM for 12 h. After replacing the serum-free medium with a complete DMEM medium, cells were treated with C3 or PBS for 48 h. Then, the culture medium was removed, and the cells were washed with cold PBS. Total protein was extracted from the cells using lysis buffer (KeyGEN Biotech, Nanjing, China), and protein quantification was performed using a BCA assay. Then, proteins (20 μg) were separated through SDS-PAGE and electrotransferred to polyvinylidene difluoride membranes. After being blocked with blocking buffers (Beyotime Institute of Biotechnology, China) for 30 min at 4°C, the membranes were incubated overnight at 4°C with primary antibodies (1:1,000) diluted in primary antibody dilution buffer (Beyotime Institute of Biotechnology, China) targeted against RIP1 (1:1,000; Cat. No. 3493T; Cell Signaling Technology, USA). Following the membranes were incubated at room temperature with an anti-rabbit IgG, HRP-conjugated antibody (1:5000; Cat. No. 7074; Cell Signaling Technology, USA.) for 1 h at room temperature, the blots were visualized using ECL western detection reagents (Thermo Fisher Scientific, USA.) in the Gel Imaging System (Licor Odyssey, USA).

Cell apoptosis analysis

Induction of C3-induced apoptosis of LLC cells was demonstrated by flow cytometry-based Annexin V/PI staining according to the instrument of the fluorescein isothiocyanate (FITC) Annexin-V/PI Apoptosis Detection Kit (BD Biosciences, San Diego, CA, USA). In summary, 4 × 105 cells were seeded in each well of a 6-well plate. After starved for 12 h, LLC cells were treated with C3 or PBS for 48 h. Further, the cells were collected and resuspended with binding buffer containing 5 μl of FITC-conjugated anti-annexin-V/PI staining antibody and 5 μl of propidium iodide solution. After 15 min incubation at room temperature and in darkness, the cell apoptotic rate was determined by flow cytometry (Beckman Coulter, IN, USA), and data were analyzed using CytExpert software.

Statistical analysis

Statistical analysis was performed with GraphPad Prism 5.0. (San Diego, CA, USA). Statistical significance between the groups was analyzed using paired Student's t-test. A P < 0.05 was considered statistically significant.


  Results Top


Identification of C3

3,3'-((4-chlorophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3), 1.69 g with the yield of 76%, white power, formula: C25H15ClO6, m. p. 259°C–261°C; ESI-MS, m/z: 447 (M + H) +; IR (KBr): 3072, 1663 (C = O),1603, 1560, 1489, 1349, 1308, 1092 cm-1; 1H-NMR (DMSO-d6, 400 MHz): δ 6.315 (s, 1H, H-11), 7.169 (dd, 2H, J = 0.8, 8.4 Hz, H-2”,6”), 7.253-7.362 (m, 6H, H-6, 6′, 8, 8′, 3′′, 5′′), 7.585 (dt, 2H, J = 1.6, 7.6 Hz, H-7,7'), 7.896 (dd, 2H, J = 1.2, 8.0 Hz, H-5,5'), 8.780 (brs, 2H, 2OH). Compared to the literature,[19] the compound is identified as 3,3'-((4-chlorophenyl)methylene) bis(4-hydroxy-2H-chromen-2-one) [Figure 1].

C3 inhibited cell proliferation

To investigated the effect of C3 on cell proliferation, NSCLC cells (LLC, A549, H460) and rat cardiomyocytes H9C2 cells were treated with PBS or various concentrations C3 (2, 4, 6, 8, 10, 12, 14, 16, and 18 μM) for 48 h. The effects of C3 on NSCLC cells viability were evaluated by performing the CCK-8 assay [Figure 2]. As shown in [Figure 2], the inhibition of cell proliferation in concentration ranges from 2 to 18 μM in NSCLC cells, C3 showed a significant inhibitory effect on the growth of LLC cells in a time and dose-dependent manner compared with the cells treating with PBS (control). Moreover, C3 has little effect on the growth of H9C2 cells. The half-maximal inhibitory concentration (IC50) of C3 was 8.754 μM for LLC cells, and 11.41 μM for A549 cells, 41.89 μM for H460 cells, for H9C2 cells, respectively. These data indicated that C3 displays a strong cytostatic effect on NSCLC cells. As the sensitive cell, LLC cells were selected for further experiments.
Figure 2: C3 suppressed lung cancer cell proliferation. Cells were cultured and treated with or without C3 for 72 h and relative cell proliferation was measured by CCK-8 assay. The cells treated with PBS as control cells. IC50 were calculated. Data are shown as the mean ± SD. CCK-8: Cell counting kit-8; PBS: Phosphate-buffered saline; SD: Standard deviation; LLC: Lewis lung cancer.

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C3-induced cell cycle arrested at G2/M

Since cell proliferation is always closely linked to the progression of the cell cycle, we evaluated the cell cycle profile of C3-induced LLC cells using FACS analysis. As shown in [Figure 3], an accumulation of S-phase and G2/M cells was observed in C3-induced culture, which was in a dose-dependent manner, while the number of G0G1 cells was decreased with C3 treatment in LLC cells. At the concentration of 5 μM, the total G2/M phase cells were enhanced from 23.71 ± 5.1 to 40.39 ± 11.31 in LLC cells. Moreover, at the concentration of 10 μM, the G2/M phase cells were enhanced from 23.71 ± 5.1 to 62.1 ± 14.27 in LLC cells. Those suggested that C3 inhibited the growth of lung cancer cells due to the arrest cell cycle at the G2/M phase.
Figure 3: C3 inhibited lung cancer cell at G2M stage. (a-c) Cells were cultured and treated with multipule concentrations of C3 for 48 h. Cell cycle distribution was measured by flow cytometry following PI staining. (d) Percentage of G1/S/G2/M cells. All data represent triplicates and are displayed as the mean ± S.E.M. *P < 0.05.

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C3-induced cell death through apoptosis

To explore the mechanism of ORFV NA1/11-induced cytotoxicity, apoptosis was examined. By flow cytometry, the apoptosis rate of LLC cells infected with C3 was increased from 6.83 ± 2.68 to 22.27 ± 2.84, 36.56 ± 11.97 compared with the control cells [Figure 4]a. By Western blot, the cleaved PARP was increased in LLC cells with C3 treatment [Figure 4]b. In order to further determine the apoptosis induced by C3, we used the pan-caspase inhibitor Z-VAD to inhibit the activation of the caspase signaling pathway, thus blocking the caspase-dependent apoptosis pathway in cells. Results showed that Z-VAD delayed the C3-induced cell death in LLC cells [Figure 4]c, though it did not rescue the cell death induced by C3. Together, these data revealed that the cytotoxic effects of C3 were associated with potentiated apoptosis capability.
Figure 4: C3-induced apoptosis. (a) Cell were treated with C3 (12 μM) for 48 h or were treated with PBS. Apoptosis was measured by flow cytometry following staining with annexin V and PI. (b) PARP and RIP1 were detected by Western blotting. GAPDH was detected as an input control. (c) Cells were pretreated with Z-VAD (10 μM) for 1 h, or remained untreated before exposure to C3. Cell viability was detected by CCK-8 assay. (d) Cells were pretreated with NEC-1 (30 μM) for 1 h, or remained untreated before exposure to C3. Cell viability was detected by CCK-8 assay. Data shown are the mean ± SD. *P < 0.05. SD: Standard deviation; CCK-8: Cell counting kit-8; PBS: Phosphate-buffered saline; LLC: Lewis lung cancer.

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Inhibition of RIP1-protected Lewis lung cancer cell from C3-induced cytotoxity

RIP1 plays a key role in the process of cell apoptosis and survival. Our previous studies found that RIP1 promotes cell survival in NSCLC cells. Therefore, we designed experiments to investigate whether the proapoptosis effects of C3 through RIP1. LLC cells treated with C3 for 48 h, and the expression of RIP1 proteins in LLC cells was evaluated. As shown in [Figure 4]c, RIP1 significantly increased after treatment with C3 at the concentrations of 5 and 10 μM in LLC cells. To further determine whether the regulation of RIP1 was required in C3-induced apoptosis, the LLC cells were treated with 40 μM C3 in the presence or absence of the necrostatin-1 (NEC-1), a potent inhibitor of RIP1. As shown in [Figure 4]d, the cell viability was decreased when LLC cells treated with C3 in the presence of NEC-1. Therefore, the results showed that the increasing of RIP1 played a vital role in C3-induced apoptosis.


  Discussion Top


It has been reported that coumarin derivatives affect different stages of cell cycle progression, such as G2/M stage and pre-G1 stage, resulting in apoptosis and death.[20],[21] Apoptosis induction can be mediated by changing the cell level of Bcl-2 family proteins, activating caspases-dependent intrinsic pathway, decreasing mitochondrial membrane protein, and increasing the expression of proapoptotic protein and intracellular reactive oxygen species.[22],[23],[24],[25] Elshemy and Zaki[26] reported novel series of 8-methoxy-coumarins, the coumarins 29 and 30 can enhance Bax and reduce Bcl-2 level by activating caspase-3 and -9, which can cause cell cycle arrest in G2/M phase and induce apoptosis. Zhang et al.[27] reported a new series of 2-cyanoacryloyl coumarin, in which coumarin 32 promoted apoptosis in MG63 by upregulating the proapoptotic protein Bax, downregulating the anti-apoptotic protein Bcl-2 and activating caspase-3, 8, and 9. Fayed et al.[28] found that a prepared coumarin can induce apoptosis by blocking the cell cycle in G2/M and enhancing the expression of caspase-3 and caspase-9.

In our study, synthesized coumarins C3 were used to test the antiproliferation of two lung cancer cell lines in vitro. Compared with the control, coumarin showed an effective inhibitory activity on LLC cells (IC50 = 0.65 μM). C3 suppressed the cell cycle progression at G2/M phase, and finally inhibited cell proliferation. It is worth emphasizing that C3 exerted its antitumor effect through apoptosis as evidenced by annexin V/PI double staining confirmed the engagement of apoptosis in cell death induction compared to control cells.

RIP1 is involved in the activation of nuclear factor κB (NF-κB) and because NF-κB usually has the anti-apoptosis effect, RIP1 is considered the mediator of cell survival. RIP1 has also been found to promote apoptosis.[29],[30],[31],[32] Therefore, RIP1 is not only a tumor-promoting factor in several cancers but also mediates either apoptosis or necroptosis in certain circumstances. RIP1 has been identified as a target for the treatment of human diseases, including cancer, in recent studies.[33],[34] Overexpression of RIP1 was found in glioblastoma and lung cancer, which is considered an endogenous tumor-promoting factor of these malignant tumors.[35],[36],[37] While RIP1 is cleaved into RIP1-N and RIP1-C at D324 by caspase 8, and this cleavage promotes apoptosis. In this report, we found that the increase of RIP1 stimulated by C3 is helpful to induce the cell death of lung cancer cells; our previous studies found that RIP1 in lung cancer plays a role in resisting the anticancer effect of chemotherapy drugs, including cisplatin.[38] Those suggested that RIP1 will transmit the signals activated by different stimuli to different pathways according to the cell environment and stimulation types, thus making the cells survive or die.

In conclusion, our study showed that the mechanism of antitumor of C3 in lung cancer cells involved cell growth suppress caused by cell cycle arrest at the G2/M phase, inducing cell apoptosis partly resulting from increased RIP1, indicating a clinical potential of C3.


  Conclusion Top


In the present study, C3 can inhibit the proliferation of LLC cells and induce G2/M phase cell cycle arrest. In addition, C3 possessed a significant reduction on cell apoptosis by increasing of RIP1 expression. In conclusion, C3 suppresses lung cancer cell proliferation and induces cell apoptosis, which is possibly involved with the RIP1. The mechanism is worthy further study.

Financial support and sponsorship

This study was financially supported by The Joint Fund of Basic and Applied Basic Research Fund of Guangdong Province (2019A1515110689), the Science and Technology Key Project of COVID-19 in Foshan city (No. 2020001000206), Regional Joint Fund-Key Project of Guangdong Basic and Applied Basic Research fund (2020B1515120033), and the Scientific Research Program of High-Level Talents of Foshan University (No. CGZ07001). The funding sources had no role in the study design, data collection, data analysis, interpretation, or writing of the report.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
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