Abstract
Objective:We aim to enhance the effectiveness of curcumin analog PGV-1 through co-treatment with diosmin, a citrus flavonoid, on 4T1 cells and evaluate the molecular targets underlying its effect on the cell cycle. Methods:Cytotoxic effects were performed by MTT assay against 4T1 cells. The May Grünwald-Giemsa staining was used to observe cell cycle arrest. The senescence was assayed with SA-ß-gal staining. Bioinformatic studies were utilized to discover protein targets of PGV-1 and diosmin on triple-negative breast cancer (TNBC) using SwissTargetPrediction, then exploration of protein targets was performed using the TCGA dataset via the UALCAN website. Kaplan-Meier was performed using GraphPad with data from the TCGA dataset via Oncoln. Using MOE 2010, we conducted the binding affinity between PGV-1 and diosmin to protein targets. Results:PGV-1 and diosmin showed cytotoxic effect with IC50 values of 9 µM and 389 µM, respectively, and the combined cytotoxic assay exhibited a synergistic effect with a combination index (CI) of <1. PGV-arrested 4T1 cells in pro-metaphase and induced mitotic catastrophe, while the combination of diosmin with PGV-1 increased the number of mitotic catastrophes. The SA-ß-gal assay revealed that both compounds were capable of inducing senescence in 4T1 cells. Study bioinformatics and molecular docking showed that PGV-1 and diosmin target cell cycle regulatory proteins in TNBC, namely CDK1, KIF11, and AURKA. Thus, the combination of diosmin and PGV-1 modulating the cell cycle that causes senescence and catastrophic death of 4T1 cancer cells is related to the inhibition of these cell cycle proteins.Conclusion:Diosmin enhances the cytotoxic effect of PGV-1 synergistically on 4T1 cancer cells, which correlates to the increasing senescence and mitotic catastrophe. The synergistic effect of the co-treatment is likely to target AURKA, CDK1, and KIF11. The combination of PGV-1 and diosmin performs a potential as a combinatorial anticancer drug for TNBC.
Highlights
Chemotherapy remains the standard approach in most breast cancer patients, especially in the triple-negative breast cancer (TNBC) subtype
Effects of Pentagamavunon-1 MTT (PGV-1) and diosmin on cells growth of 4T1 cells To evaluate the cytotoxic effect of diosmin and PGV-1, we performed an MTT assay in the concentration range of 10-500 μM for diosmin and 0.5-16 μM for PGV-1 using 4T1 cells, which are known not to express estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) (Kulkarni et al, 2019)
A combination cytotoxic test was carried out to evaluate the effect of diosmin on PGV-1 in inhibiting the proliferation of 4T1 cancer cells
Summary
Chemotherapy remains the standard approach in most breast cancer patients, especially in the triple-negative breast cancer (TNBC) subtype. Doxorubicin intercalates with DNA base pairs and causes DNA damage leading to the activation of various molecular signals to induce apoptosis (Tacar et al, 2012) as well as cisplatin, which causes DNA damage on cells by forming cross-linking covalent bonds on purine bases in 1,2-intrastrand DNA (Hu et al, 2016). Both chemotherapy drugs targeted DNA is held by normal cells. Developing new chemotherapeutic agents for TNBC treatment with low side effects and a high effectivity and selectivity is a great challenge
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