Unlocking vinpocetine's oncostatic potential in early-stage hepatocellular carcinoma: A new approach to oncogenic modulation by a nootropic drug – PubMed Black Hawk Supplements

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The development of new drugs for the inhibition of hepatocellular carcinoma (HCC) development and progression is a critical and urgent need. The median survival rate for HCC patients remains disappointingly low. Vinpocetine is a safe nootropic agent that is often used to enhance cognitive function. The impact of vinpocetine on HCC development and progression has not been fully explored. Our main objective was to investigate the possible inhibitory role of vinpocetine in rats exposed to…
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Unlocking vinpocetine's oncostatic potential in early-stage hepatocellular carcinoma: A new approach to oncogenic modulation by a nootropic drug - PubMed

Unlocking vinpocetine’s oncostatic potential in early-stage hepatocellular carcinoma: A new approach to oncogenic modulation by a nootropic drug

Osama A Mohammed et al. PLoS One. .

Abstract

The development of new drugs for the inhibition of hepatocellular carcinoma (HCC) development and progression is a critical and urgent need. The median survival rate for HCC patients remains disappointingly low. Vinpocetine is a safe nootropic agent that is often used to enhance cognitive function. The impact of vinpocetine on HCC development and progression has not been fully explored. Our main objective was to investigate the possible inhibitory role of vinpocetine in rats exposed to diethylnitrosamine. We observed that vinpocetine increased the survival rate of these rats and improved the ultrastructure of their livers. Additionally, vinpocetine reduced the liver weight index, mitigated liver oxidative stress, and improved liver function. In both in vitro and in vivo settings, vinpocetine demonstrated antiproliferative and apoptotic properties. It downregulated the expression of CCND1 and Ki-67 while exhibiting anti-BCL-2 effects and enhancing the levels of Bax and cleaved caspase-3. Vinpocetine also successfully deactivated NF-κB, STAT3, and HIF-1α, along with their associated transcription proteins, thereby exerting anti-inflammatory and anti-angiogenic role. Furthermore, vinpocetine showed promise in reducing the levels of ICAM-1 and TGF-β1 indicating its potential role in tissue remodeling. These findings strongly suggest that vinpocetine holds promise as a hepatoprotective agent by targeting a range of oncogenic proteins simultaneously. However, further approaches are needed to validate and establish causal links between our observed effects allowing for a more in-depth exploration of the mechanisms underlying vinpocetine’s effects and identifying pivotal determinants of outcomes.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Impact of progressive vinpocetine dosage escalation on HepG2 cell viability.

(A) a decline in HepG2 cell viability with escalating vinpocetine dosage and consequential augmentation in cell inhibition rates. (B) cellular proliferation at varying vinpocetine concentrations over 24, 48, 72-hour intervals. (C) LDH Activity at a gradual elevation of vinpocetine concentration. Data are presented as mean ± SD (n = 3). Statistical analysis was performed using ordinary one-way ANOVA, followed by Tukey’s posthoc test. ****p 0.0001; **p 0.01.

Fig 2
Fig 2. Effects of vinpocetine on CCND1 (A), Cleaved Caspase-3 (B), and Caspase-1 Activity (C) Levels in HepG2 Cells.

Data are presented as mean ± SD (n = 6). Statistical analysis was performed using ordinary one-way ANOVA, followed by Tukey’s posthoc test. ***p 0.001; *p 0.05.

Fig 3
Fig 3. Histological score (A); liver ultrastructure examination in different experimental groups stained with H&E stain (B); Fibrosis area % as quantified using ImageJ software (C); Sirius Red-stained liver sections (D).

scale bar = 50 μm. Data were analyzed with the Mann-Whitney test and are expressed as the median ± IQR for histological score (n = 6). Data were analyzed using ordinary one-way ANOVA, followed by Tukey’s posthoc test and are presented as mean ± SD for fibrosis area % (n = 6). ****, p 0.0001; ***, p 0.001; **, p 0.01; *, p 0.05.

Fig 4
Fig 4. Vinpocetine mitigated liver weight index (A), AFP (B), MDA (C) and ROS (D) and improved SOD (E) and GSH (F).

It also improved liver function by mitigating ALT (G), AST (H), γGT (I) in DENA-intoxicated rats. Data are presented as mean ± SD (n = 6). Statistical analysis was performed using ordinary one-way ANOVA, followed by Tukey’s posthoc test. ****, p 0.0001; ***, p 0.001; **, p 0.01; *, p 0.05.

Fig 5
Fig 5

Impact of vinpocetine on Ki-67 labeling index (A) and tissue expression (B). VEGF hepatic level (C) and mRNA expression (D) confirm the findings of VEGF labeling index (E) and immunohistochemical labeling (F). Data are presented as mean ± SD (n = 6). Statistical analysis was performed using ordinary one-way ANOVA, followed by Tukey’s posthoc test. ****, p 0.0001; ***, p 0.001; **, p 0.01; *, p 0.05.

Fig 6
Fig 6. Effects of vinpocetine on DENA-induced oncogenic molecular alterations in rats.

Panels (A) through (I) depict changes in NF-κB p65 DNA-binding activity, IL-6 levels, MCP-1 expression, ICAM-1 expression, TGF-β expression, HIF-1α levels, MMP-9 levels, STAT3 mRNA levels, and p-STAT3 levels, respectively. Data are presented as mean ± SD (n = 6). Statistical analysis was performed using ordinary one-way ANOVA, followed by Tukey’s posthoc test. ****, p < 0.0001; ***, p < 0.001; **, p < 0.01; *, p < 0.05.

Fig 7
Fig 7. This figure demonstrates the changes in expression levels of CCND1 (A), BCL-2 (B), and Bax (C) following DENA administration and subsequent vinpocetine treatment in rat liver tissues.

Data are presented as mean ± SD (n = 6). Statistical analysis was performed using ordinary one-way ANOVA, followed by Tukey’s posthoc test. ****p 0.0001; **p 0.01; *p 0.05.

Fig 8
Fig 8. This figure illustrates the impact of vinpocetine treatment on caspase-3 labeling index (A) as determined by immunostaining (B) and cleaved caspase-3 levels (C) in DENA-exposed rats.

Data are presented as mean ± SD (n = 6). Statistical analysis was performed using ordinary one-way ANOVA, followed by Tukey’s posthoc test. ****p 0.0001; **p 0.01.

Fig 9
Fig 9. Vinpocetine improves survival rate in DENA-exposed rats.

The administration of DENA led to a gradual decrease in rats’ survival over the experimental period. However, treatment with vinpocetine significantly enhanced the survival rate of rats exposed to DENA.

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The authors are thankful to the Deanship of Graduate Studies and Scientific Research at University of Bisha for supporting this work through the Fast-Track Research Support Program. The authors would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work. This work was supported by the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia (Grant No. GrantA420).

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Unlocking vinpocetine's oncostatic potential in early-stage hepatocellular carcinoma: A new approach to oncogenic modulation by a nootropic drug – PubMed