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. 2023 Jun 21;28(13):4900.
doi: 10.3390/molecules28134900.

Combination of Lycopene and Curcumin Synergistically Alleviates Testosterone-Propionate-Induced Benign Prostatic Hyperplasia in Sprague Dawley Rats via Modulating Inflammation and Proliferation

Shanshan Wang  1 , Wenjiang He  2 , Wenzhi Li  2 , Jin-Rong Zhou  3 , Zhiyun Du  1   4   5
Affiliations

Combination of Lycopene and Curcumin Synergistically Alleviates Testosterone-Propionate-Induced Benign Prostatic Hyperplasia in Sprague Dawley Rats via Modulating Inflammation and Proliferation

Shanshan Wang et al. Molecules. .

Abstract

Background: Benign prostatic hyperplasia (BPH) is a progressive urological disease occurring in middle-aged and elderly men, which can be characterized by the non-malignant overgrowth of stromal and epithelial cells in the transition zone of the prostate. Previous studies have demonstrated that lycopene can inhibit proliferation, while curcumin can strongly inhibit inflammation. This study aims to determine the inhibitory effect of the combination of lycopene and curcumin on BPH.

Method: To induce BPH models in vitro and in vivo, the BPH-1 cell line and Sprague Dawley (SD) rats were used, respectively. Rats were divided into six groups and treated daily with a vehicle, lycopene (12.5 mg/kg), curcumin (2.4 mg/kg), a combination of lycopene and curcumin (12.5 mg/kg + 2.4 mg/kg) or finasteride (5 mg/kg). Histologic sections were examined via hematoxylin and eosin (H&E) staining and immunohistochemistry. Hormone and inflammatory indicators were detected via ELISA. Network pharmacology analysis was used to fully predict the therapeutic mechanism of the combination of lycopene and curcumin on BPH.

Results: Combination treatment significantly attenuated prostate hyperplasia, alleviated BPH pathological features and decreased the expression of Ki-67 in rats. The upregulation of the expression of testosterone, dihydrotestosterone (DHT), 5α-reductase, estradiol (E2) and prostate-specific antigen (PSA) in BPH rats was significantly blocked by the combination treatment. The expression levels of inflammatory factors including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were strongly inhibited by the combination treatment. From the network pharmacology analysis, it was found that the main targets for inhibiting BPH are AKT1, TNF, EGFR, STAT3 and PTGS2, which are enriched in pathways in cancer.

Conclusion: The lycopene and curcumin combination is a potential and more effective agent to prevent or treat BPH.

Keywords: BPH; curcumin; inflammation; lycopene; synergistic effect.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Effects of LY and CUR on the viability of BPH-1 cells. (A) The dose-dependent effect of LY on cell viability; (B) the dose-dependent effect of CUR on cell viability; (C) the effect of LY/CUR combinations on cell viability. All values are means ± SD (n = 6). Within each panel, the values with the superscription symbol are significantly different from that of the control; * p < 0.05, ** p < 0.01 and *** p < 0.001.
Figure 2
Figure 2
Effects of experimental treatments on BPH development in rats. (A) Prostatic weight; (B) prostate index; (C) quantified results of epithelium thickness of prostate (ETP); (D) time-dependent body weight change; (E) body weight of rats at week 8; (F) representative H&E staining images. All values are mean ± SD (n = 6). Within each panel (A–C), the values with the superscription symbols are significantly different from those of the corresponding control; * p < 0.05, ** p < 0.01 and *** p < 0.001, when compared with the BPH group; ### p < 0.001, compared with the CON group; one-way ANOVA followed by Tukey’s comparison test.
Figure 3
Figure 3
Effects of experimental treatments on serum levels of hormones. (A) Dihydrotestosterone (DHT), (B) 5α-reductase, (C) testosterone (T), (D) estradiol (E2) and (E) prostate-specific antigen (PSA) in rats. All values are mean ± SD (n = 6). # p < 0.05 vs. CON group, * p < 0.05, ** p < 0.01 vs. BPH group, one-way ANOVA followed by Tukey’s comparison test.
Figure 4
Figure 4
Assessment of treatment effects on serum levels of inflammatory cytokines TNF-α (A), IL-1β (B) and IL-6 (C). All values are mean ± SD (n = 6). # p < 0.05 vs. CON group, * p < 0.05, ** p < 0.01, *** p < 0.001 vs. BPH group, one-way ANOVA followed by Tukey’s comparison test.
Figure 5
Figure 5
Immunohistochemistry (IHC) of prostatic tissues. (A) Animal prostates were collected and stained by cell proliferation marker Ki-67, in rats treated by (a) control group (CON), (b) BPH model group (BPH), (c) BPH+FN group (FN), (d) BPH+LY group (LY), (e) BPH+CUR group (CUR) or (f) BPH + LY + CUR group (COM), respectively. The arrows point to brown areas representing the expression of Ki-67. (B) Quantitative analysis of gray value was carried out by ImageJ. All values are mean ± SD (n = 3). ### p < 0.001 vs. CON group, * p < 0.05, ** p < 0.01 vs. BPH group, one-way ANOVA followed by Tukey’s comparison test.
Figure 6
Figure 6
The predicted molecular candidate targets between the BPH- and LY-associated targets (A), or between the BPH- and CUR-associated targets (B).
Figure 7
Figure 7
Protein–protein interaction network. The PPI network was constructed using Cytoscape and analyzed using NetworkAnalyzer. Different colors represent the degree. Node size is proportional to the degree of interaction.
Figure 8
Figure 8
KEGG enrichment analysis of the anti-BPH targets of lycopene and curcumin.
Figure 9
Figure 9
Experimental flow chart.
Figure 10
Figure 10
Molecular mechanism diagram.
See this image and copyright information in PMC

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