scholarly journals Cryptolepine inhibits hepatocellular carcinoma growth through inhibiting interleukin-6/STAT3 signalling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Seth A. Domfeh ◽  
Patrick W. Narkwa ◽  
Osbourne Quaye ◽  
Kwadwo A. Kusi ◽  
Gordon A. Awandare ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Interleukin 6 ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Human Hepatoma Cells ◽  
Cryptolepis Sanguinolenta ◽  
Anti Cancer ◽  
Dose Dependent Fashion ◽  
Cancer Intervention ◽  
Stat3 Signalling

Abstract Background Diverse signalling pathways are involved in carcinogenesis and one of such pathways implicated in many cancers is the interleukin 6/signal transducer and activator of transcription 3 (IL-6/STAT3) signalling pathway. Therefore, inhibition of this pathway is targeted as an anti-cancer intervention. This study aimed to establish the effect of cryptolepine, which is the main bioactive alkaloid in the medicinal plant Cryptolepis sanguinolenta, on the IL-6/STAT3 signalling pathway. Methods First, the effect of cryptolepine on the IL-6/STAT3 pathway in human hepatoma cells (HepG2 cells) was screened using the Cignal Finder Multi-Pathway Reporter Array. Next, to confirm the effect of cryptolepine on the IL-6/STAT3 signalling pathway, the pathway was activated using 200 ng/mL IL-6 in the presence of 0.5–2 μM cryptolepine. The levels of total STAT3, p-STAT3 and IL-23 were assessed by ELISA. Results Cryptolepine downregulated 12 signalling pathways including the IL-6/STAT3 signalling pathway and upregulated 17 signalling pathways. Cryptolepine, in the presence of IL-6, decreased the levels of p-STAT3 and IL-23 in a dose-dependent fashion. Conclusion Our results demonstrated that cryptolepine inhibits the IL-6/STAT3 signalling pathway, and therefore cryptolepine-based remedies such as Cryptolepis sanguinolenta could potentially be used as an effective immunotherapeutic agent for hepatocellular carcinoma and other cancers.

scholarly journals Cryptolepine consolidates its anticancer potential by increasing the anti-cancer pathway genes and decreasing that of pro-cancer pathway genes

2021 ◽  
Author(s):  
Patrick Williams Narkwa ◽  
Seth Agyei Domfeh ◽  
Gordon Awandare ◽  
Mohamed Mutocheluh
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Signalling Pathways ◽  
Pharmacological Activities ◽  
Middle Income ◽  
Transcript Levels ◽  
Cryptolepis Sanguinolenta ◽  
Anti Cancer ◽  
Negative Side Effects

Abstract Background: Cancers are one of the commonest causes of deaths globally. Reports indicate that greater than sixty percent of cancers in the world occur in low and middle-income countries with about seventy percent of all cancer deaths occurring in these regions. Conventional cancer treatments involve surgery, radiotherapy, chemotherapy, etc. However, the negative side effects such as high cost and toxicity associated with these treatment options have increased the demand for less toxic and less expensive anti-cancer drugs from natural sources. One of such natural products believed to have anti-cancer potential is cryptolepine (CRYP), an alkaloid extracted from the roots of Western and Central African plant Cryptolepis sanguinolenta. In addition to its anti-cancer potential, CRYP has been reported to possess a myriad of pharmacological activities. However, the mechanisms underlying the anti-cancer and pharmacological activities of CRYP have not been fully explored. Methods: We screened 45 immune and cancer signalling pathways for their regulation following treatment with CRYP using the dual-luciferase based Cignal Finder Multi-Pathway Reporter Arrays to pinpoint which pathways are regulated by CRYP. Additionally, the effects of CRYP on the transcript levels of interferon regulatory factor 1 (IRF-1), progesterone receptor (PR), hypoxia-inducible factor-1 alpha (HIF-1α) and signal transducer and activator of transcription 3 (STAT 3) were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Results: We observed that of the 45 immune and cancer signalling pathways screened, nine were up-regulated while twenty-seven were down-regulated by CRYP. However, CRYP had no effect on nine of the pathways screened. We also observed that CRYP induced an increase in the transcript levels of IRF1 and PR but decreased that of HIF1-α and STAT3. Conclusion: The upregulation of human anti-cancer pathway genes including IRF-1 and PR and concomitant down-regulation of pro-cancer pathway genes including HIF1-α and STAT3 suggest additional mechanisms through which CRYP could exhibits its anti-cancer potential.

scholarly journals Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

2018 ◽  
Author(s):  
Ellie Paige ◽  
Marc Clément ◽  
Fabien Lareyre ◽  
Michael Sweeting ◽  
Juliette Raffort ◽  
...  
Keyword(s):  
Mouse Models ◽  
Interleukin 6 ◽  
Aortic Rupture ◽  
Minor Allele ◽  
Aortic Aneurysms ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Abdominal Aortic ◽  
Interleukin 6 Receptor ◽  
Age And Sex

AbstractBackgroundThe Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture.MethodUsing data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.ResultsAfter adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [−0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).ConclusionsOur proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

scholarly journals Cryptolepine consolidates its anticancer potential by increasing the anti-cancer pathway genes and decreasing that of pro-cancer pathway genes

2021 ◽  
Author(s):  
Patrick Williams Narkwa ◽  
Seth Agyei Domfeh ◽  
Gordon Awandare ◽  
Mohamed Mutocheluh
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Signalling Pathways ◽  
Pharmacological Activities ◽  
Middle Income ◽  
Transcript Levels ◽  
Cryptolepis Sanguinolenta ◽  
Anti Cancer ◽  
Negative Side Effects

Abstract Background: Cancers are one of the commonest causes of deaths globally. Reports indicate that greater than sixty percent of cancers in the world occur in low and middle-income countries with about seventy percent of all cancer deaths occurring in these regions. Conventional cancer treatments involve surgery, radiotherapy, chemotherapy, etc. However, the negative side effects such as high cost and toxicity associated with these treatment options have increased the demand for less toxic and less expensive anti-cancer drugs from natural sources. One of such natural products believed to have anti-cancer potential is cryptolepine (CRYP), an alkaloid extracted from the roots of Western and Central African plant Cryptolepis sanguinolenta. In addition to its anti-cancer potential, CRYP has been reported to possess a myriad of pharmacological activities. However, the mechanisms underlying the anti-cancer and pharmacological activities of CRYP have not been fully explored. Methods: We screened 45 immune and cancer signalling pathways for their regulation following treatment with CRYP using the dual-luciferase based Cignal Finder Multi-Pathway Reporter Arrays to pinpoint which pathways are regulated by CRYP. Additionally, the effects of CRYP on the transcript levels of interferon regulatory factor 1 (IRF-1), progesterone receptor (PR), hypoxia-inducible factor-1 alpha (HIF-1α) and signal transducer and activator of transcription 3 (STAT 3) were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Results: We observed that of the 45 immune and cancer signalling pathways screened, nine were up-regulated while twenty-seven were down-regulated by CRYP. However, CRYP had no effect on nine of the pathways screened. We also observed that CRYP induced an increase in the transcript levels of IRF1 and PR but decreased that of HIF1-α and STAT3. Conclusion: The upregulation of human anti-cancer pathway genes including IRF-1 and PR and concomitant down-regulation of pro-cancer pathway genes including HIF1-α and STAT3 suggest additional mechanisms through which CRYP could exhibits its anti-cancer potential.

Synergistic Antitumor Effect of 5-Fluorouracil Combined with Constituents from Pleurospermum lindleyanum in Hepatocellular carcinoma SMMC-7721 Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Xiao-Feng Zhu ◽  
Xiao-Jin Li ◽  
Zhong-Lian Cao ◽  
Xiu-Jie Liu ◽  
Ping Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Effectiveness ◽  
Synergistic Effects ◽  
Folk Medicine ◽  
Inhibitory Effect ◽  
Caspase 9 ◽  
Whole Plant ◽  
Anti Cancer ◽  
Induced Apoptosis

Background: A Chinese folk medicine plant Pleurospermum lindleyanum possesses pharmacological activities of heat-clearing, detoxifying and preventing from hepatopathy, coronary heart disease, hypertension, and high altitude sickness. We isolated and characterized its constituents to investigate its synergistic effects against human hepatoma SMMC-7721 cells. Objective: The aim of this study was to explore the synergistic anti-cancer activities of isolates from P. lindleyanum with 5-FU on hepatoma SMMC-7721 cells in vitro and their primary mechanisms. Methods: Sequential chromatographic techniques were conducted for the isolation studies. The isolates structures were established by spectroscopic analysis as well as X-ray crystallographic diffraction. Growth inhibition was detected by MTT assay. The isobologram method was used to assess the effect of drug combinations. Flow cytometry and western blot were used to examine apoptosis and protein expression. Results: A new coumarin (16), along with sixteen known compounds, were isolated from the whole plant of P. lindleyanum and their structures were elucidated by spectroscopic methods. Four coumarins (2, 3, 5, and 16), two flavonoids (8 and 9) and three phytosterols and triterpenes (12-14) were found to synergistically enhance the inhibitory effect of 5-FU against SMMC-7721 cells. Among them, compounds 3 and 16 exhibited the best synergistic effects with IC50 of 5-FU reduced by 16-fold and 22-fold possessing the minimum Combination Index (CI) 0.34 and 0.27. The mechanism of action of combinations might be through synergistic arresting for the cell cycle at G1 phases and the induction of apoptosis. Moreover, western blotting and molecular docking revealed that compounds 3 or 5 might promote 5-FU-induced apoptosis by regulating the expression of Caspase 9 and PARP. Conclusion: Constituents from P. lindleyanum may improve the treatment effectiveness of 5-FU against hepatocellular carcinoma cells.

Sign in / Sign up

Export Citation Format

Share Document