Potential use of compounds from sea cucumbers as MDM2 and CXCR4 inhibitors to control cancer cell growth

Abstract

Ineffectiveness of cancer therapy may originate in the incompatibility of the treatment with various mutations in the cancer cells. Finding novel anticancer treatments that work efficiently for varying types of cancer cells remains challenging. Previous studies have identified that compounds in sea cucumbers are capable of inhibiting the growth of cancer cells and inducing apoptosis. However, information on the underlying mechanisms controlling cancer cell growth at a molecular level remains limited. The current study analyzed the potential of colochiroside A, ds-echinoside A, philinopside E, sphingosine and stichoposide C as inhibitors for anticancer target proteins, including mouse double minute 2 homolog (MDM2) and C-X-C chemokine receptor type 4 (CXCR4). Inhibition of MDM2 triggers apoptosis through regulation of tumor protein 53 and CXCR4 inhibition may prevent cancer cell proliferation and growth by affecting the Janus kinase 2/3 signal transducer and activator of transcription signaling pathway and protein tyrosine kinase 2. The results of a binding affinity analysis using molecular docking revealed that philinopside E and ds-echinoside A may inhibit MDM2 and CXCR4. The data suggested that these active compounds may be promising inhibitors of cell growth by binding to two targets simultaneously. Furthermore, stichoposide C and colochiroside A were predicted to inhibit CXCR4. Additional research is needed to validate the in vitro activity of the aforementioned compounds.

Keywords: BioGRID; C-X-C chemokine receptor type 4; Janus kinase 2/3; anticancer; apoptosis; mouse double minute 2 homolog; pathway analysis; sea cucumber.

Figure 1.

Interaction between MDM2 and compounds from sea cucumbers. Docking of (A) a tetra-substituted imidazole, a known MDM2 inhibitor, (B) ds-echinoside A and (C) philinopside E to MDM2. At the top, MDM2 presented in green ribbon structure with ligands presented as red spheres. In the middle, hydrophobicity surface map of the active site of MDM2 with the ligands presented as red cylinders. At the bottom, cylinder representation of the ligands with carbon atoms in grey, nitrogen in blue, chlorine in green, oxygen in red and hydrogen in white, to emphasize ligand orientation. MDM2, mouse double minute 2 homolog.

Figure 2.

Interaction between CXCR4 and compounds from sea cucumbers. Docking of (A) chalcone-4, a known CXCR4 inhibitor, (B) colochiroside A, (C) philinopside E, (D) ds-echinoside A and (E) stichoposide C to CXCR4. At the top, CXCR4 presented in blue ribbon structure with ligands presented as red spheres. In the middle, hydrophobicity surface map of the active site of CXCR4 with the ligands presented as red cylinders. At the bottom, cylinder representation of the ligands with carbon atoms in grey, nitrogen in blue, chlorine in green, oxygen in red and hydrogen in white, to emphasize ligand orientation. CXCR4, C-X-C chemokine receptor type 4.

Figure 3.

CXCR4 binding proteins. (A) CXCR4 protein interaction obtained from the BioGrids Database. (B) List of proteins which interact with CXCR4 based on BioGrids Database. CXCR4, C-X-C chemokine receptor type 4.

Figure 4.

CXCR4-protein interaction network. (A) Network of CXCR4 interactions based on the String Database which involve the Jak-STAT (red) and Chemokine signaling pathways (violet). (B) Calculated number of genes involved in various pathways connected to the CXCR4 network. (C) Genes identified to participate in the Jak-STAT and chemokine signaling pathways. The false discovery rates were also determined. CXCR4, C-X-C chemokine receptor type 4; Jak-STAT, Janus kinase signal transducer and activator of transcription.

Figure 5.

Anticancer mechanism of compounds from sea cucumbers through inhibition of (A) MDM2 or (B) CXCR4. Inhibition of both proteins may lead to decreased cell migration, cell proliferation, cell growth and angiogenesis, which may lead to apoptosis. MDM2, mouse double minute 2 homolog; CXCR4, C-X-C chemokine receptor type 4; p53, tumor protein 53; CXCL12, C-X-C motif chemokine 12; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PTK2, protein tyrosine kinase 2.