Apigenin's Modulation of Doxorubicin Efficacy in Breast Cancer

Abstract

Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores apigenin's capacity to modulate cancer cell viability, emphasizing its roles beyond its minimal antioxidant activity attributed to its basic molecular structure devoid of hydroxyl groups. We investigated apigenin's effects on two breast cancer cell lines, estrogen-dependent MCF-7 and non-estrogen-dependent MDA-MB-231 cells. Our findings reveal that apigenin exerts a dose-dependent cytotoxic and anti-migratory impact on these cells. Interestingly, both apigenin and doxorubicin-a standard chemotherapeutic agent-induced lipid droplet accumulation in a dose-dependent manner in MDA-MB-231 cells. This phenomenon was absent in MCF-7 cells and not evident when doxorubicin and apigenin were used concurrently, suggesting distinct cellular responses to these treatments that imply that their synergistic effects might be mediated through mechanisms unrelated to lipid metabolism. A further chemoinformatics analysis indicated that apigenin and doxorubicin might interact primarily at the level of ATP-binding cassette (ABC) transporter proteins, with potential indirect influences from the AKT and MYC signaling pathways. These results highlight the importance of understanding the nuanced interactions between apigenin and conventional chemotherapeutic drugs, as they could lead to more effective strategies for cancer treatment. This study underscores apigenin's potential as a modulator of cancer cell dynamics through mechanisms independent of its direct antioxidant effects, thereby contributing to the development of flavonoid-based adjunct therapies in cancer management.

Keywords: anticancer; breast cancer treatment; flavonoids; nutrition; synergistic effects.

Figure 1

Cancer cell viability of the MCF-7 and MDA-MB-231 cell lines post-24 h of DOX exposure.

Figure 2

Morphological changes in the MCF-7 cell line following a 24 h incubation with Api.

Figure 3

Cell viability after 24 h of DOX (IC25) and Api simultaneous treatment in MDA-MB-231 (A) and MCF-7 (B) cell lines. Significance * p < 0.05; ** p < 0.01; *** p < 0.0005; **** p < 0.0001, n = 3, compared to the control group.

Figure 4

Isobologram method of determining synergy in the MDA-MB-231 (A) and MCF-7 cell lines (B).

Figure 5

Changes in scratch width within the MDA-MB-231 (A) and MCF-7 (B) cell monolayer over time at 0, 16, and 24 h in the presence of the studied substances and without the added compound (control).

Figure 6

Concentration-dependent effects of Api (A) and DOX (B) on cell migration speed in the MDA-MB-231 cell line and MCF-7 cell line. Negative migration values indicate a cytotoxic effect at the corresponding concentration.

Figure 7

Lipid accumulation after 24 h of treatment across two cell lines treated by Api alone (A), DOX (B), or the simultaneous treatment with DOX and Api (C). Simple linear regression analysis between treatment concentration and lipid accumulation in the cells is shown.

Figure 8

Protein–protein interaction network with DOX and Api. Interactions are represented in grey (protein–protein) and green (chemical–protein) lines, where line thickness signifies the strength of evidence. Data were derived from STITCH 5.0, with a high-confidence interaction score threshold (≥0.700).