6-Shogaol enhances the chemotherapeutic efficacy of 5-fluorouracil through apoptosis induction and cell cycle arrest in MCF-7 breast cancer cells

• 6-shogaol effectively inhibited the growth of breast cancer MCF-7 cells by inducing apoptosis and G2/M phase cell cycle arrest • 6-shogaol exhibited greater selectivity toward cancer cells compared with non-cancerous cells • 6-shogaol synergistically enhanced the anti-cancer activity of 5-FU, leading to significant dose reduction and augmented apoptosis at extended treatment times Ginger ( Zingiber officinale ) has a long history of use in Traditional Chinese Medicine (TCM) as a “cure-all remedy”. 6-Shogaol, an essential bioactive element from dried ginger, has been widely used in traditional Chinese medicinal preparations. 6-Shogaol has been reported to exhibit anticancer properties, including induction of apoptosis and epigenetic regulation. However, its potential in combination with standard chemotherapeutic agents against breast cancer remains unclear. This study aimed to investigate the antiproliferative effects of 6-shogaol alone and in combination with 5-fluorouracil (5-FU) or cisplatin in MCF-7 cells and to explore its underlying mechanisms of action. Cell viability was assessed using MTT assays, while apoptosis and cell cycle progression were evaluated by annexin V-FITC/PI staining and PI staining, respectively, followed by flow cytometric analysis. Combination effects were determined using the Chou–Talalay method to obtain combination index (CI) and dose reduction index (DRI). 6-Shogaol significantly inhibited MCF-7 cell proliferation in a dose- and time-dependent manner and demonstrated higher selectivity toward cancer cells than non-cancerous Vero cells. Mechanistic studies revealed that 6-shogaol induced apoptosis and G2/M cell cycle arrest. Combination treatment with 5-FU showed moderate synergistic effects (CI = 0.80 and 0.70 at 48 and 72 h, respectively) resulting in substantial dose reduction of 5-FU (>20-fold) and enhanced apoptosis at 72 h. By contrast, the combination of 6-shogaol and cisplatin exhibited antagonistic effects (CI > 1), with no additional benefit compared to single-agent treatment. These findings demonstrate that 6-shogaol is a promising natural compound capable of selectively suppressing breast cancer cell growth and potentiating the anticancer efficacy of 5-FU. The synergistic combination highlights its potential as an adjuvant strategy to reduce chemotherapeutic dosage and minimize toxicity, warranting further investigation in vivo and in clinical settings.