Marimastat

Numerous side effects of breast cancer drugs have prompted researchers to explore more into new therapeutic approaches derived from natural substances. In this context, our study focused on uncovering the potential of East Kalimantan propolis from Trigona apicalis for breast cancer treatment including the underlying mechanisms through bioinformatics approached. We conducted integrated in vitro and bioinformatics analysis of network pharmacology, molecular docking, molecular dynamics and MM-GBSA analysis. Initially, in vitro cytotoxic assay demonstrated the anti-breast cancer activity potential of ethanol extract of East Kalimantan propolis, particularly its ethyl acetate fraction, which exhibited similar activity to doxorubicin, as indicated by their IC₅₀ value. This study revealed eight propolis compounds, consisting of flavonoids and phenolic acids, in East Kalimantan propolis. By integrating microarray datasets (GSE29431, GSE36295, and GSE42568) analysis with potential targets derived from propolis compounds, 39 shared target genes were identified. Subsequently, GO and KEGG pathway, protein-protein interaction (PPI) network, core hub genes and gene expression analysis revealed three major targets, namely, PTGS2, CXCL2, and MMP9. Among them, only MMP9 was highly expressed in breast cancer than normal. Moreover, molecular docking revealed the six of propolis compounds which exhibited pronounced binding affinity towards MMP-9, better than marimastat as control drug. Dynamic simulation confirmed the stability of chrysin and quercetin as best compounds. Additionally, MM-GBSA analysis revealed a relative binding energy for chrysin (-25.6403 kcal/mol) that was comparable to marimastat (-27.3827 kcal/mol). In conclusion, this study reveals how East Kalimantan Propolis affect breast cancer and emphasizes MMP9 as a key target for future therapeutics.

We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors as well as from their destination host tissues. Therefore, the gene products involved are potential targets for anti‐metastasis drug treatment.

Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components.

Individually, the low‐specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16‐F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci.

The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers.