Chelerythrine Chloride Inhibits Stemness of Melanoma Cancer Stem-Like Cells (CSCs) Potentially via Inducing Reactive Oxygen Species and Causing Mitochondria Dysfunction

Li, Hong; He, Mei; Zhao, Pengyu; Liu, Ping; Chen, Wei; Xu, Xuewen

doi:https://doi.org/10.1155/2022/4000733

Computational and Mathematical Methods in Medicine

On this page

Abstract Introduction Methods Results Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Special Issue

Leveraging Complexity and Heterogeneity in Multi-Omics Biomedical Data

View this Special Issue

Research Article | Open Access

Volume 2022 | Article ID 4000733 | https://doi.org/10.1155/2022/4000733

Chelerythrine Chloride Inhibits Stemness of Melanoma Cancer Stem-Like Cells (CSCs) Potentially via Inducing Reactive Oxygen Species and Causing Mitochondria Dysfunction

Hong Li,¹Mei He,¹Pengyu Zhao,¹Ping Liu,¹Wei Chen,¹and Xuewen Xu²

Academic Editor: Jialiang Yang

Received19 Jan 2022

Revised27 Mar 2022

Accepted18 Apr 2022

Published18 Jun 2022

Abstract

Growing evidence has demonstrated that high heterogeneity contributes to poor prognosis and malignancies. The existence of melanoma cancer stem-like cells (CSCs), which are a small subpopulation of melanoma cells, is responsible for tumour resistance to therapies. Recently, plant secondary metabolites have attracted attention because they are considered promising compounds that are isolated from herbs that could help to target different subpopulations of tumours. In the present study, we aimed to identify the antitumourigenic activities of the medicinal compound chelerythrine chloride (CHE) on melanoma CSCs. CHE (30-40 μmol/L) induced apoptosis in A375 and A2058 CSCs. A relatively low dose of CHE (1-5 μmol/L) inhibited the stemness of melanoma CSCs without inducing apoptosis. Coculture of CHE with A375 and A2058 cells also inhibited sphere formation and decreased stemness factors, including Nanog, Oct4, and Sox2. In functional characterizations, we observed that CHE treatment increased both cellular reactive oxygen species (ROS) and mitochondrial ROS, which resulted in a decrease in mitochondrial energy production and sphere formation. Abolishing CHE-induced ROS by N-acetyl-L-cysteine (NAC), a ROS scavenger, reversed the inhibitory effects of CHE on sphere formation, suggesting that CHE-induced ROS are the potential cause of the inhibition of sphere formation. In conclusion, CHE may exert its antitumour effect as an antistem cell natural compound, suggesting that selection of the antistem cell effects of natural compounds might be a promising strategy to overcome the poor prognosis of melanoma due to the presence of CSCs.

1. Introduction

Malignant melanoma (MM) is a highly aggressive form of skin cancer that continues to increase rapidly worldwide. Intratumoural heterogeneity is believed to be one of the key reasons for this aggressiveness in malignant melanoma. In fact, tumour cells are organized and maintained in layers by subpopulations of cells termed cancer stem cells (CSCs or tumour initiating cells). These cells have stem cell-like functional properties, such as self-renewal and multipotency [1, 2]. The existence of CSCs is believed to contribute to tumour initiation, maintenance, progression, metastasis, and recurrence. Moreover, because of their unique biological characteristics, CSCs remarkably result in an increase in radioresistance and chemoresistance, which leads to poor prognosis. In addition, the CSC phenotype of the tumour is not a strict state, and the intratumoural heterogeneity of the tumour extends to CSC features, mainly due to the tumour microenvironment (TME) [3]. Melanoma CSCs are mainly characterized by upregulated levels of surface stem factors, including Nanog, Sox2, and Oct4, and their sphere formation capacity in vitro and in vivo [4, 5].

Although major efforts have been made in recent decades, useful therapeutic strategies targeting melanoma CSCs to address chemoresistance and radioresistance, which cause poor prognosis, remain challenging. Several candidate strategies have been proposed, but few have been applied clinically [6]. In treating glioblastoma stem cells, Pizzocri and colleagues employed drug-loaded liposomes and aimed to trigger an in situ immune response [7]. This method was found to be an effective strategy to deliver cytotoxic molecules to GSCs at the surgical tumour margins, which are the forefront of glioblastoma (GBM) recurrence, circumventing blood–brain barrier hurdles. Carrillo-Gálvez reported that glycoprotein A repetitions predominant (GARP) is a potential target on the surface of human osteo-, chondro-, and undifferentiated pleomorphic sarcomas. Targeting GARP in bone sarcomas could reduce tumour burden while simultaneously improving the efficacy of chemo- and radiotherapy [8]. All these results demonstrate that targeting CSCs is a potential and efficient strategy to overcome chemo- and radioresistance, which cause poor prognosis.

The last decades of research have led to the identification of a specific population of cancer cells endowed with the capability to self-renew and differentiate that are highly responsible for tumour growth and progression [9]. These cells, known as CSCs, possess intrinsic resistance to chemo- and radiotherapy, have high metastatic potential, and result in tumour relapse after treatment. Previously considered to be a small population, CSCs appear to be heterogeneous and sometimes numerous within specific types of cancer [10]. Due to their high plasticity, CSCs may experience phases of transition between stem-like and non-stem-like states. Furthermore, increasing evidence demonstrates that bulk tumour cells can acquire a stem cell-like phenotype in response to exogenous stimuli. This finding suggests that the process of cancer cell differentiation can be reversed and further contributes to cancer heterogeneity [9–11]. Altogether, considerable controversy remains as to how unequivocally define CSCs and to what extent distinct tumour types possess a hierarchical organization. Nevertheless, a growing body of evidence indicates that stem cell-associated molecular features, collectively known as stemness, are biologically important in cancer development and progression [9–11].

Natural herbs with a variety of biological and physiological effects have been widely employed in clinical practice for thousands of years worldwide. Traditional Chinese medicine is considered one of the most ancient medicines. Radix Astragali, Radix Ginseng, and Radix Codonopsis play an important role and exert significant therapeutic effects in melanoma therapy through many mechanisms and targets [12]. CHE is one of the main constituents of the genus Chelidonium L. [13], which can also be extracted from the herbs Toddalia asiatica (Linn) Lam [14] and Macleaya cordata (Willd.) R. Br [15]. CHEs have shown a variety of effects, including antitumour [16], antibacterial [14], anti-inflammatory [13], pesticidal, and antihepatic fibrosis effects [17], and certain protective effects against diabetic cardiomyopathy [18–20]. Due to its antitumour effects, CHE can inhibit the proliferation of lung cancer [21], liver cancer [22], and breast cancer cells [16] and induce apoptosis [19].

There is still a lack of research on the treatment of malignant melanoma with CHE [19]. It has been reported that CHE leads to ROS generation and accumulation, resulting in the inhibition of cell proliferation, reduction of colony formation, and induction of cell apoptosis [23]. In this study, we evaluated the effects of CHE on the stemness of melanoma CSCs by regulating ROS levels and mitochondrial function.

2. Material and Methods

2.1. Cell Culture and Enrichment of CSCs

Human melanoma A2058 and A375 cells were kept in culture dish (Corning Incorporated Life Sciences, Tewksbury, MA, USA), with the presence of 10% () fetal bovine serum (FBS, Gibco, Carlsbad, CA), 100 units/mL penicillin, and 100 μg/mL streptomycin at 37°C under 100% humidity. Cells were passaged every 2-3 days.

For sphere formation, melanoma cells were seeded in 6-well plates (Corning Incorporated Life Science, NY, USA) and cultured in DMEM/F-12 (Gibco) without addition of FBS and supplemented 2% () B27, 10 ng/mL EGF, and 20 ng/mL bFGF. Medium was half-refreshed every 2-3 days.

2.2. Cell Viability

To evaluate cell viability, CCK-8 assay (Sigma Aldrich) was employed. Briefly, cells were seeded in 96-well plates and allowed to be cultured at 37°C under 100% humidity overnight. After 24, 48, 72, 96, or 120 h, 10 μL of CCK-8 reagent was added to the medium and allowed for 2-hour incubation at 37°C. Then, the absorbance was read at 450 nm using the microplate reader (Bio-Rad, Milan, Italy).

2.3. Cellular and Mitochondrial ROS Quantification

To evaluate cellular ROS level, ROS-Glo H₂O₂ assay kit (Promega, Madison, WI, USA) was employed following the manufacturer’s protocol. Detectable signal was analysed using Polarstar Optima plate reader (BMG LABTECH, Ortenberg, Germany). To analyse mitochondrial ROS, MitoSOX Red staining (Thermo Fisher) was employed following the manufacturer’s protocol. Briefly, 5 μmol/L of MitoSOX Red was added into medium for 10-minute incubation at 37°C and quantitatively measured using FACSCanto II.

2.4. Western Blot

20 μg of total protein for each sample was fractionated by using 8-12% gradient SDS-PAGE, and fractionated bands were transferred onto a PVDF membrane, which was blocked by 5% () skim milk. Then, membrane was incubated in primary antibodies (1 : 1000 in 5% skim milk in TBST) at room temperature for 2 hrs. The antibodies employed were listed as follows: anti-Nanog antibody (ab109250, Abcam), anti-Sox2 antibody (ab92494, Abcam), anti-Oct4 antibody (ab109183, Abcam), and anti-β-actin antibody (Ab8226, Abcam). Then, the membrane was incubated with HRP-conjugated secondary antibody (1 : 10000, Ab270144, Abcam) for 2 hrs at room temperature followed by enhanced chemiluminescent detection (Millipore, Billerica, MA, U.S.A.).

2.5. Apoptosis

To evaluate cellular apoptosis rate, Annexin V-FITC/PI Apoptosis Detection Kit (Abcam, Cambridge, England) was used. cells were collected, washed with ice-cold PBS for three times, and resuspended in staining buffer with addition of Annexin V-FITC and PI according to the manufacturer’s instructions. After 30 min incubation at room temperature avoiding light, cells were analysed by performing flow cytometry with 3 laser Navios flow cytometers (Beckman Coulter, Brea, CA, USA) in 30 min.

2.6. ATP Measurement

To quantitatively measure total ATP synthesis, ATP detection kit (LT07-221, ViaLight Plus kit, Lonza, Basel, Switzerland) was employed following the manufacturer’s protocol. Briefly, cells were lysed for one vial analysis. Chemiluminescence was read in an FL ×800 microplate fluorescence reader (BioTek, Winooski, VT, USA).

2.7. Statistical Analysis

The experiments were performed at least five times for a reliable application of statistics. All samples used were included in the statistical analysis. Statistical analysis was performed by test, one-way analysis of variance (ANOVA), and two-way ANOVA with GraphPad Prism 6 software, as specified in each figure legend. Statistical significances were accepted at . Values are presented as mean of independent .

3. Results

3.1. Cancer Stem-Like Cells Derived from Melanoma Cells Are Sensitive to CHE

To obtain CSCs from A375 and A2058 cells, CSCs were enriched by culturing in serum-free medium and formed spheres were collected separately after 14 days (Figure 1(a)). In enriched A375 and A2058 CSCs, stem factors including Nanog, Oct4, and Sox2 were obviously increased compared with those in A375 and A2058 parental cells (Figure 1(b)). By performing cell viability assay, it was observed that enriched CSCs present slight decrease in A375 and A2058 CSCs compared with those in A375 and A2058 (Figure 1(c)).

(a)

(b)

(c)

To access CHE sensitivity to PCs or CSCs, 5-40 μmol/L of CHE was cocultured with PCs or CSCs for 24 h and then cell viability was measured. It is observed that lower CHE concentration induced decrease in A375 and A2058 CSCs compared to those in A375 and A2058 PCs (Figures 2(a) and 2(b)). Notably, 30 μmol/L of CHE slightly caused cellular apoptosis in both A375 and A2058 CSCs (Figure 2(c)), which indicated that low concentration of CHE (<30 μmol/L) mainly induce cell cycle arrest but not apoptosis.

(a)

(b)

(c)

3.2. Relative Low Concentration of CHE Inhibits Stemness of Melanoma CSCs without Disturbing Cell Viability

To confirm the effects of CHE on stemness maintenance of CSCs derived from melanoma cells, we treated A375 and A2058 CSCs using 1-5 μmol/L of CHE for 7 days. Morphologically, it is observed that CHE treatment decreased the formation of spheres and reduced the diameter of sphere observed (Figure 3(a)). To confirm whether the reduction of sphere formation is caused by cytotoxicity, CCK-8 assay was performed to evaluate the cell viability after 24 h treatment of different concentrations of CHE. Expectedly, 1-3 μmol/L of CHE exerts no obvious effect on cell viability, while 4 and 5 μmol/L of CHE decreased cell viability (Figure 3(b)). After a 7-day treatment, stem factors including Nanog, Oct4, and Sox2 were also decreased by 1-5 μmol/L of CHE treatment (Figure 3(c)), indicating that 1-3 μmol/L of CHE decreases stemness of melanoma CSCs without affecting cell viability.

(a)

(b)

(c)

3.3. CHE Inhibits Sphere Formation of Melanoma Cells

To evaluate whether CHE inhibits sphere formation of melanoma cells, we cultured melanoma cells in serum-free medium with the addition of 3 μmol/L of CHE for 4-day incubation. Images were taken at the same position to observe the processes of sphere formation. As it is shown in Figures 4(a) and 4(b), the addition of CHE obviously inhibited sphere formation while melanoma cells were still stably attached to the bottom of wells, suggesting that CHE inhibits sphere formation, but does not exert cytotoxicity. CCK-8 assay further confirmed that CHE treatment slightly affected cell viability for 1-3 days (Figure 4(c)). It is expectedly observed that, after a 5-day incubation, stem factors including Nanog, Oct4, and Sox2 were not obviously upregulated when compared to the mock group (data not shown).

(a)

(b)

(c)

3.4. CHE Inhibits Intracellular and Mitochondrial ROS and Reduced ATP Synthesis

To examine the effects of CHE on cellular physiological processes, we examined the accumulation of cellular or mitochondrial ROS. We analysed cellular ROS and mitochondrial ROS, respectively. As it is shown in Figures 5(a) and 5(b), it is observed that the addition of 3 μmol/L of CHE significantly increased both cellular and mitochondrial ROS levels. By adding NAC to 10 μmol/L, the inhibitory effect of CHE on sphere formation was reversed (Figure 5(c)), suggesting that CHE-induced ROS accumulation is critical for its inhibitory role in stemness potentially via disturbing mitochondrial function.

(a)

(b)

(c)

Taken together, all results demonstrate that CHE affects stemness of melanoma CSCs potentially via inducing ROS accumulation and subsequently caused mitochondria-related energy disturbance.

4. Discussion

CHE exerts antitumour effects on various human tumour cell lines by inhibiting cell proliferation and inducing apoptosis [22, 24, 25]. However, its effects on CSCs are still largely unknown [25–27], which causes challenges and problems for its applications. In this study, we studied the in vitro effects of CHE on the stemness of melanoma CSCs and its potential mechanism of action. The addition of a relatively low concentration of CHE, which presents undetectable cytotoxicity and antitumour effects on melanoma cells, significantly reduced the stemness of melanoma CSCs, including A375 and A2058 CSCs. These results suggest that CHE regulates the maintenance of stemness in melanoma CSCs. Moreover, pretreatment with CHE inhibited sphere formation of melanoma cells. These findings further suggest that CHE not only inhibited stemness of melanoma CSCs but also inhibited sphere formation of CSCs.

In a previous report, chelerythrine hydrochloride (CHE) was shown to exert inhibitory effects on non-small-cell lung carcinoma- (NSCLC-) derived CSCs [28]. The dose–response pattern of CHE in three NSCLC cell lines showed a similar overall pattern of cytotoxicity and growth arrest over the entire concentration range, suggesting that CHE cytotoxicity exists globally. We examined the inhibitory effect of 5 to 40 μmol/L CHE on cell viability in melanoma parental cells and related CSCs. Melanoma CSCs were more sensitive to the effects of CHE. A relatively low dose of CHE inhibited cell viability in both A375 and A2058 CSCs but not in their parental cells. Moreover, CHE failed to induce cell apoptosis, indicating that effects of CHE on cell viability were potentially due to blockage of cell cycle distribution. As a limitation of this study, we failed to analyse cell cycle distribution. We also observed that after treatment with chelerythrine at low concentrations, the spheres of melanoma cells disintegrated instead of undergoing cell death. There is one possible reason for this particular effect: the addition of CHE-differentiated melanoma cells and differentiated melanoma cancer cells results in tolerance to CHE.

The effects of CHE on CSCs were previously investigated. Zhu and colleagues reported that in NSCLC CSCs, CHE treatment downregulated the expression of Sox2, MYC, and β-catenin, which are critical stem factors. These results suggest that CHE may reduce CSC properties and induce apoptosis via the Wnt/β-catenin pathway [29]. In this study, we observed significant downregulation of Sox2 expression in melanoma CSCs and the expression of two other stem factors, Nanog and Oct4, which are critical for maintaining stemness. However, a decrease in β-catenin was not observed (data not shown), potentially due to the low endogenous level of β-catenin. To mimic the cytoplasmic accumulation and nuclear localization of β-catenin, we used GSK3i, a GSK3β inhibitor, to stimulate β-catenin levels. Surprisingly, the addition of GSK3i failed to induce β-catenin (data not shown), potentially because β-catenin is not critically regulated by GSK3β-β-catenin signalling.

Previous studies have demonstrated that ROS induce cell apoptosis by affecting mitochondrial function in cancer cells [30, 31], and CHE was reported to cause cell death by accumulating ROS in NSCLC cells [23]. In this study, consistent with previous findings, CHE treatment significantly induced cellular ROS and mitochondrial ROS accumulation in melanoma CSCs. Moreover, CHE treatment-induced inhibition of sphere formation was reversed by the addition of NAC, which is an ROS scavenger. These findings suggest that CHE-induced ROS are critical for the inhibitory role of CHE in the stemness of melanoma CSCs. Induction of ROS production from nicotinamide adenine dinucleotide phosphate oxidase, mitochondria, cyclooxygenase, etc., or a reduction in the scavenging capacity of ROS contributed to the intercellular accumulation of ROS [23, 32, 33]. Catalase is an enzyme that breaks down hydrogen peroxide in cells. This produces intercellular reactive oxygen species by selectively degrading the protein expression of catalase, leading to cell death [34]. Mitochondrial ROS, in most cases, enhance prosurvival autophagy and thus reduce cell apoptosis [35]. These findings indicate that the origin of ROS induced by CHE treatment may lead to different consequences in cancer therapy. In this study, intracellular ROS and mitochondrial ROS were all induced by CHE. This finding may explain why a relatively low dose of CHE inhibits cell proliferation and stemness but does not induce apoptosis. This issue should be clarified in the future. CHE critically affects mitochondria and malignancies in melanoma CSCs and is well recognized as a potent inhibitor of protein kinase C (PKC) for isoforms α and β. However, its effect on normal cells is still missing and worth investigating in further studies. CHE was also demonstrated to exert cell death-promoting effects in different manners, including apoptosis [36, 37] and necrotic-like cell death [38]. We only demonstrated the effects of CHE on apoptosis with or without NAC, although CHE treatment obviously induced necrotic-like cell death (Figure 2(c)). This also requires further investigation.

5. Conclusion

In this study, we observed that CHE probably inhibited melanoma CSC growth and stemness by inducing ROS accumulation and regulating mitochondrial function and energy production. CHE is considered an inhibitor of melanoma CSCs but also prevents melanoma cells from developing into melanoma CSCs. In further studies, we will identify the exact role of intracellular ROS and mitochondrial ROS in CSC fate to determine the optimal use of CHE in the clinical setting.

Data Availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

HL, XWX, and MH designed the experiments. HL, PYZ, PL, and WC performed cell culture-associated experiments. PYZ and WC are responsible for data collection and performed the statistical analysis. All authors read and approved the final manuscript. HL, XWX, and PL confirmed the authenticity of all the raw data.

Acknowledgments

This study was supported by the Program of Innovative Subject of Young People in Medical Research in Sichuan Province (grant no. Q17009).

References

A. Allegra, A. Alonci, G. Penna et al., “The cancer stem cell hypothesis: a guide to potential molecular targets,” Cancer Investigation, vol. 32, no. 9, pp. 470–495, 2014.
View at: Publisher Site | Google Scholar
F. Islam, V. Gopalan, R. Smith, and A. K. Y. Lam, “Translational potential of cancer stem cells: a review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment,” Experimental Cell Research, vol. 335, no. 1, pp. 135–147, 2015.
View at: Publisher Site | Google Scholar
P. Hernández-Camarero, G. Jiménez, E. López-Ruiz, S. Barungi, J. A. Marchal, and M. Perán, “Revisiting the dynamic cancer stem cell model: importance of tumour edges,” Critical Reviews in Oncology/Hematology, vol. 131, pp. 35–45, 2018.
View at: Publisher Site | Google Scholar
T. Schatton, G. Murphy, N. Frank et al., “Identification of cells initiating human melanomas,” Nature, vol. 451, no. 7176, pp. 345–349, 2008.
View at: Publisher Site | Google Scholar
G. Civenni, A. Walter, N. Kobert et al., “Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth,” Cancer Research, vol. 71, no. 8, pp. 3098–3109, 2011.
View at: Publisher Site | Google Scholar
S. Lim, J. Lee, R. Diefenbach, R. F. Kefford, and H. Rizos, “Liquid biomarkers in melanoma: detection and discovery,” Molecular Cancer, vol. 17, no. 1, p. 8, 2018.
View at: Publisher Site | Google Scholar
M. Pizzocri, F. Re, E. Stanzani et al., “Radiation and adjuvant drug-loaded liposomes target glioblastoma stem cells and trigger in-situ immune response,” Neurooncol Adv, vol. 3, no. 1, p. vdab076, 2021.
View at: Publisher Site | Google Scholar
A. Carrillo-Gálvez, J. Quintero, R. Rodríguez et al., “GARP promotes the proliferation and therapeutic resistance of bone sarcoma cancer cells through the activation of TGF-β,” Cell Death & Disease, vol. 11, no. 11, p. 985, 2020.
View at: Publisher Site | Google Scholar
P. Czerwińska and B. Kamińska, “Regulation of breast cancer stem cell features,” Contemporary Oncology, vol. 19, no. 1A, pp. A7–A15, 2015.
View at: Publisher Site | Google Scholar
G. Lee, R. Hall, and A. Ahmed, “Cancer stem cells: cellular plasticity, niche, and its clinical relevance,” J Stem Cell Res Ther, vol. 6, no. 10, pp. 363–383, 2016.
View at: Publisher Site | Google Scholar
P. Czerwińska, S. Mazurek, and M. Wiznerowicz, “Application of induced pluripotency in cancer studies,” Rep Pract Oncol Radiother, vol. 23, no. 3, pp. 207–214, 2018.
View at: Publisher Site | Google Scholar
X. Zhang, W. Liu, H. Jiang, and B. Mao, “Chinese herbal medicine for advanced non-small-cell lung cancer: a systematic review and meta-analysis,” The American Journal of Chinese Medicine, vol. 46, no. 5, pp. 923–952, 2018.
View at: Publisher Site | Google Scholar
A. Banerjee, S. Sanyal, S. Dutta et al., “The plant alkaloid chelerythrine binds to chromatin, alters H3K9Ac and modulates global gene expression,” Journal of Biomolecular Structure & Dynamics, vol. 35, no. 7, pp. 1491–1499, 2017.
View at: Publisher Site | Google Scholar
N. He, P. Wang, P. Wang, C. Ma, and W. Kang, “Antibacterial mechanism of chelerythrine isolated from root of Toddalia asiatica (Linn) Lam,” BMC Complementary and Alternative Medicine, vol. 18, no. 1, p. 261, 2018.
View at: Publisher Site | Google Scholar
M. Khin, A. Jones, N. Cech, and L. K. Caesar, “Phytochemical analysis and antimicrobial efficacy ofMacleaya cordataagainst extensively drug-resistantStaphylococcus aureus,” Natural Product Communications, vol. 13, no. 11, p. 1934578X1801301, 2018.
View at: Publisher Site | Google Scholar
W. Lin, J. Huang, Z. Yuan, S. Feng, Y. Xie, and W. Ma, “Protein kinase C inhibitor chelerythrine selectively inhibits proliferation of triple-negative breast cancer cells,” Scientific Reports, vol. 7, no. 1, p. 2022, 2017.
View at: Publisher Site | Google Scholar
P. Wang, Z. Yin, and W. Kang, “Advance in studies on pharmacological activities of chelerythrine,” Zhongguo Zhong Yao Za Zhi, vol. 38, no. 17, pp. 2745–2749, 2013.
View at: Google Scholar
Q. Zhang, Y. Tian, J. Duan et al., “Chelerythrine ameliorates acute cardiac allograft rejection in mice,” Transplant Immunology, vol. 38, pp. 78–83, 2016.
View at: Publisher Site | Google Scholar
N. Hatae, E. Fujita, S. Shigenobu et al., “Antiproliferative activity of _O_ ₄-benzo[ _c_ ]phenanthridine alkaloids against HCT-116 and HL-60 tumor cells,” Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 14, pp. 2749–2752, 2015.
View at: Publisher Site | Google Scholar
A. Kemény-Beke, J. Aradi, J. Damjanovich et al., “Apoptotic response of uveal melanoma cells upon treatment with chelidonine, sanguinarine and chelerythrine,” Cancer Letters, vol. 237, no. 1, pp. 67–75, 2006.
View at: Publisher Site | Google Scholar
M. He, Z. Yang, L. Zhang, C. Song, Y. Li, and X. Zhang, “Additive effects of cherlerythrine chloride combination with erlotinib in human non-small cell lung cancer cells,” PLoS One, vol. 12, no. 4, article e0175466, 2017.
View at: Publisher Site | Google Scholar
Z. Zhang, Y. Guo, J. Zhang, and X. H. Wei, “Induction of apoptosis by chelerythrine chloride through mitochondrial pathway and Bcl-2 family proteins in human hepatoma SMMC-7721 cell,” Archives of Pharmacal Research, vol. 34, no. 5, pp. 791–800, 2011.
View at: Publisher Site | Google Scholar
Z. Tang, W. Cao, Z. Wang et al., “Induction of reactive oxygen species-stimulated distinctive autophagy by chelerythrine in non-small cell lung cancer cells,” Redox Biology, vol. 12, pp. 367–376, 2017.
View at: Publisher Site | Google Scholar
S. J. Chmura, M. E. Dolan, A. Cha, H. J. Mauceri, D. W. Kufe, and R. R. Weichselbaum, “In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo,” Clinical Cancer Research, vol. 6, no. 2, pp. 737–742, 2000.
View at: Google Scholar
J. Malikova, A. Zdařilová, A. Hlobilkova, and J. Ulrichova, “The effect of chelerythrine on cell growth, apoptosis, and cell cycle in human normal and cancer cells in comparison with sanguinarine,” Cell Biology and Toxicology, vol. 22, no. 6, pp. 439–453, 2006.
View at: Publisher Site | Google Scholar
L. Gao, H. Schmitz, K. Merz, and D. Schrenk, “Characterization of the cytotoxicity of selected _Chelidonium_ alkaloids in rat hepatocytes,” Toxicology Letters, vol. 311, pp. 91–97, 2019.
View at: Publisher Site | Google Scholar
P. Kosina, D. Walterová, J. Ulrichová et al., “Sanguinarine and chelerythrine: assessment of safety on pigs in ninety days feeding experiment,” Food and Chemical Toxicology, vol. 42, no. 1, pp. 85–91, 2004.
View at: Publisher Site | Google Scholar
W. Heng and S. Cheah, “Chelerythrine chloride downregulates β-catenin and inhibits stem cell properties of non-small cell lung carcinoma,” Molecules, vol. 25, no. 1, p. 224, 2020.
View at: Publisher Site | Google Scholar
J. Zhu, S. Wang, Y. Chen et al., “miR-19 targeting of GSK3β mediates sulforaphane suppression of lung cancer stem cells,” The Journal of Nutritional Biochemistry, vol. 44, pp. 80–91, 2017.
View at: Publisher Site | Google Scholar
Y. Chen, E. McMillan-Ward, J. Kong, S. J. Israels, and S. B. Gibson, “Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells,” Cell Death and Differentiation, vol. 15, no. 1, pp. 171–182, 2008.
View at: Publisher Site | Google Scholar
R. Nair, M. Emmons, A. Cress et al., “HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells,” Molecular Cancer Therapeutics, vol. 8, no. 8, pp. 2441–2451, 2009.
View at: Publisher Site | Google Scholar
R. Chen, W. Ding, and F. McCormick, “Wnt signaling to β-catenin involves two interactive components:,” The Journal of Biological Chemistry, vol. 275, no. 23, pp. 17894–17899, 2000.
View at: Publisher Site | Google Scholar
N. Goode, K. Hughes, J. Woodgett, and P. J. Parker, “Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes,” The Journal of Biological Chemistry, vol. 267, no. 24, pp. 16878–16882, 1992.
View at: Publisher Site | Google Scholar
T. He, A. Sparks, C. Rago et al., “Identification of c-MYCas a target of the APC pathway,” Science, vol. 281, no. 5382, pp. 1509–1512, 1998.
View at: Publisher Site | Google Scholar
B. Weaver, “How taxol/paclitaxel kills cancer cells,” Molecular Biology of the Cell, vol. 25, no. 18, pp. 2677–2681, 2014.
View at: Publisher Site | Google Scholar
S. Yamamoto, K. Seta, C. Morisco, S. F. Vatner, and J. Sadoshima, “Chelerythrine rapidly induces apoptosis through generation of reactive oxygen species in cardiac myocytes,” Journal of Molecular and Cellular Cardiology, vol. 33, no. 10, pp. 1829–1848, 2001.
View at: Publisher Site | Google Scholar
J. Vrba, P. Doležel, J. Vičar, M. Modrianský, and J. Ulrichová, “Chelerythrine and dihydrochelerythrine induce G1 phase arrest and bimodal cell death in human leukemia HL-60 cells,” Toxicology In Vitro, vol. 22, no. 4, pp. 1008–1017, 2008.
View at: Publisher Site | Google Scholar
M. Garcia-Belinchón, M. Sánchez-Osuna, L. Martínez-Escardó et al., “An early and robust activation of caspases heads cells for a regulated form of necrotic-like cell death,” The Journal of Biological Chemistry, vol. 290, no. 34, pp. 20841–20855, 2015.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Hong Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

355

Downloads

536

Citations