{Reference Type}: Journal Article
{Title}: Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells.
{Author}: Salim EI;Alabasy MM;Nashar EME;Al-Zahrani NS;Alzahrani MA;Guo Z;Beltagy DM;Shahen M;
{Journal}: BMC Complement Med Ther
{Volume}: 24
{Issue}: 1
{Year}: 2024 May 6
{Factor}: 2.838
{DOI}: 10.1186/s12906-024-04453-x
{Abstract}: <B>BACKGROUND: </B>Cancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative.<BR><B>OBJECTIVE: </B>In this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7.<BR><B>METHODS: </B>An integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene.<BR><B>METHODS: </B>We applied a systems-based analysis to introduce a drug-target-pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis.<BR><B>RESULTS: </B>The mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22).<BR><B>CONCLUSIONS: </B>Our data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.