Danshen Injection for 5-Fluorouracil-Resistant Gastric Cancer: Mitochondrial Apoptosis and Enhanced Drug Activity.
Abstract
Gastric cancer ranks among the leading causes of cancer-related death worldwide, and the progressive emergence of 5-fluorouracil (5-FU) resistance represents a critical barrier to the efficacy of conventional chemotherapy, particularly 5-FU-based regimens. Danshen injection (DI), a clinically approved intravenous preparation derived from Salvia miltiorrhiza, has demonstrated preliminary antineoplastic activity; however, the mechanistic basis underlying its reversal of 5-FU resistance in gastric cancer has not been systematically defined. This study aimed to evaluate the antitumor efficacy of DI and its potential for enhanced combined activity with 5-FU in human gastric cancer cell lines (SGC7901 and BGC823), their 5-FU-resistant variants, and a xenograft mouse model. DI significantly induced apoptosis in both parental and drug-resistant cell lines, while CCK-8 assays confirmed markedly elevated IC50 values in resistant variants, validating the chemoresistant phenotype. The combination of DI and 5-FU produced enhanced antitumor effects superior to either agent alone, as demonstrated by increased apoptotic rates, upregulated expression of cleaved PARP and cleaved caspase-3, impaired mitochondrial membrane potential by JC-10 assay, and reduced colony formation. Mechanistically, DI promoted cytochrome c translocation from mitochondria to the cytoplasm, and elevated cleaved caspase-9 levels, effects that were further amplified upon co-treatment with 5-FU. Consistent antitumor activity was validated in vivo, with the combination regimen demonstrating superior tumor suppression compared with monotherapy. Collectively, these findings demonstrate that DI exerts meaningful antitumor activity and produces a greater combined effect with 5-FU in 5-FU-resistant gastric cancer. This study provides a preclinical rationale for incorporating DI into chemotherapy-based strategies for the management of 5-FU-resistant gastric cancer.