Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells

Cancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative. In this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics...

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Published in:	BMC complementary and alternative medicine Vol. 24; no. 1; p. 185
Main Authors:	Salim, Elsayed I, Alabasy, Mona M, Nashar, Eman M El, Al-Zahrani, Norah S, Alzahrani, Mohammed A, Guo, Zihu, Beltagy, Doha M, Shahen, Mohamed
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 06-05-2024 BioMed Central BMC
Subjects:	Anticancer properties Antidiabetics Antineoplastic Agents - pharmacology Antineoplastic drugs Antitumor activity Apoptosis Apoptosis - drug effects Bcl-2 protein Biological products Breast cancer Breast Neoplasms - drug therapy Cancer therapies Cell culture Cell proliferation Cell Proliferation - drug effects Comparative analysis Cyclohexenes - pharmacology Cytotoxicity D-limonene Diabetes therapy Drug–target–pathway network Female Flow cytometry Gene analysis Gene expression Gene flow Genes Glucose Hep G2 Cells Hepatocytes HepG2 Humans Insulin Kinases Limonene Limonene - pharmacology Liver cancer Liver Neoplasms - drug therapy MCF-7 MCF-7 Cells Metformin Metformin - pharmacology Molecular interactions Mortality Natural products Nitric-oxide synthase p53 Protein Pharmacology Proteins Synergistic effect Terpenes - pharmacology Tumor cell lines Tumor proteins United States > US D-limonene HepG2 Drug–target–pathway network Metformin MCF-7 Gene analysis
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Summary:	Cancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative. 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. An integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene. 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. 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). 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2662-7671 2662-7671 1472-6882
DOI:	10.1186/s12906-024-04453-x