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. 2023 Nov 23;13(1):20612.
doi: 10.1038/s41598-023-46841-2.

New cytotoxic dammarane type saponins from Ziziphus spina-christi

Abeer H Elmaidomy  1 , Amr El Zawily  2   3 , Aliasger K Salem  4 , Faisal H Altemani  5 , Naseh A Algehainy  5 , Abdullah H Altemani  6 , Mostafa E Rateb  7 , Usama Ramadan Abdelmohsen  8   9 , Nourhan Hisham Shady  10
Affiliations

New cytotoxic dammarane type saponins from Ziziphus spina-christi

Abeer H Elmaidomy et al. Sci Rep. .

Abstract

Cancer is the world's second-leading cause of death. Drug development efforts frequently focus on medicinal plants since they are a valuable source of anticancer medications. A phytochemical investigation of the edible Ziziphus spina-christi (F. Rhamnaceae) leaf extract afforded two new dammarane type saponins identified as christinin E and F (1, 2), along with the known compound christinin A (3). Different cancer cell lines, such as lung cancer (A549), glioblastoma (U87), breast cancer (MDA-MB-231), and colorectal carcinoma (CT-26) cell lines, were used to investigate the extracted compounds' cytotoxic properties. Our findings showed significant effects on all the tested cell lines at varying concentrations (1, 5, 10, and 20 µg/mL). The three compounds exhibited potent activity at low concentrations (< 10 μg/mL), as evidenced by their low IC50 values. To further investigate the complex relationships between these identified cancer-relevant biological targets and to identify critical targets in the pathogenesis of the disease, we turned to network pharmacology and in silico-based investigations. Following this, in silico-based analysis (e.g., inverse docking, ΔG calculation, and molecular dynamics simulation) was performed on the structures of the isolated compounds to identify additional potential targets for these compounds and their likely interactions with various signalling pathways relevant to this disease. Based on our findings, Z. spina-christi's compounds showed promise as potential anti-cancer therapeutic leads in the future.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Structures of compounds isolated from Ziziphus spina-christi.
Figure 2
Figure 2
Selected HMBC (formula image) correlations of compound 2.
Figure 3
Figure 3
The anticancer activities of the three pure compounds (1–3) isolated from Ziziphus spina-christi using the MTS assay on glioblastoma, breast cancer, lung, and colorectal carcinoma cells. Cancer cells lines A549 (a) U87 (b), MDA-MB-231 (c) and CT-26 (b) were tested. Cells (2 × 104 cells per well in 96 well plates) were treated with pure compounds as using the following concentrations (1, 5, 10 or 20 μg/mL) or a matching solvent control for 24 h at 37 °C with 5% CO2. Cells were stained with MTS reagents and cell survival was quantitated using the spectramax plate reader. The graphs represent the analysis of six replicates and show the percentage of survival of A549, U87, MDA-MB-231 and CT-26–- treated cells relative to matching solvent-treated cells. The solvent used is methanol. All experiments were performed at least two times. *p < 0.05, Student’s t-test.
Figure 4
Figure 4
(A) Human cancer PPI network. This network comprises 306 nodes and 7602 edges with an average node degree of 49.7. The top-interacting nodes were colored by red (7.9%, 38 proteins of all interacting nodes, i.e., hub protein). (B) The top interacting-nodes (i.e., hub nodes arranged by their degree value). Green arrows represent the proteins predicted as probable targets for saponins aglycone investigated in the presented study. The thickness of the lines (i.e., edges) represents the degree of confidence (i.e., the strength of data support).
Figure 5
Figure 5
Subnetworks derived from the complete cancer-relevant network in Fig. 4. These networks represent the first 4 key pathways involved in cancer pathogenesis according to the presented PPI networking in Fig. 4. The thickness of the lines (i.e., edges) represents the degree of confidence (i.e., the strength of data support). Nodes encircled with red line in the PI3K-Akt signaling pathway cluster are CDK6 and HRAS that were predicted to be potential targets for compound 3.
Figure 6
Figure 6
Subnetworks derived from the complete cancer-relevant network in Fig. 4. These networks represent the second 5 key pathways involved in the cancer pathogenesis according to the presented PPI networking in Fig. 4. The thickness of the lines (i.e., edges) represents the degree of confidence (i.e., the strength of data support).
Figure 7
Figure 7
(A) PPI network showing the interactions among the 38 hub proteins characterized in the complete cancer PPI network in Fig. 4 including both GLO1 and BDR3 that were identified as a probable target for saponins aglycone. Lemon-green-colored nodes represent proteins that show interactions with BDR3, while the red-colored ones are not. GLO1 (the blue-colored node) do not show any interactions. (B) The structures of saponins aglycone along with the structures of the four proteins predicted to be potential target for it.
Figure 8
Figure 8
Binding modes of saponins aglycone (brick red-colored structure) in alignment with the co-crystalized inhibitors (cyan-colored structures) inside BDR3, CDK6, GLO1, and HRAS ((A–D), respectively).
Figure 9
Figure 9
RMSDs of saponins aglycone and the co-crystalized inhibitors inside BDR3, CDK6, GLO1, and HRAS ((A–D), respectively) over the course of 100 ns-long MD simulations.
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