Shandougen Kushen Decoction Combined with HIPEC Inhibits HIF-1α-Mediated Glycolysis in Colorectal Cancer Peritoneal Metastases.

OBJECTIVE

This study investigates the role and mechanism of Shandougen Kushen Decoction Injection (SKDI) in Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for the treatment of colorectal peritoneal metastatic cancer. This represents the first such report.

METHODS

We utilized network pharmacology to explore SKDI's metabolic targets and regulatory mechanisms for treating peritoneal metastatic cancer. Human colorectal cancer cells HCT116 and SW620 were used for in vitro assays, including CCK8, colony formation, apoptosis, cell cycle, lactic acid production, and glucose content assays. An in vivo mouse model with luciferase-labeled HCT116 cells was established to monitor tumor growth. The study compared control, heating alone (H), H+5-Fluorouracil (5FU) (simulated HIPEC), H+SKDI, and H+5FU+SKDI (combined treatment) groups for effects on cell activity, glycolytic products, and glucose uptake. Tumor growth was assessed using small animal imaging. Key targets, HIF-1α, PKM2, HK2, and LDHA, were analyzed through qRT-PCR and Western blot experiments. Further evaluation assessed the effects of HIF-1α overexpression on glycolysis and cell viability. Immunohistochemistry was used to assess the impact on key glycolysis targets at the tissue level.

RESULTS

Network pharmacology identified HK2, PKM2, and LDHA as SKDI's core glycolytic targets, regulated through the HIF-1α signaling pathway. SKDI inhibited colorectal cancer cell activity in a time-dependent manner, enhancing the effects of 5FU under hyperthermia. The combination of SKDI and 5FU under hyperthermia further inhibited clone formation and lactic acid production, induced apoptosis and G2/M cell cycle arrest, and reduced glucose content. in vivo, SKDI combined with HIPEC significantly reduced tumor size and alleviated 5FU's toxic side effects, including weight loss in mice. SKDI markedly downregulated HIF-1α and glycolytic gene/protein expression. HIF-1α overexpression led to increased glycolysis, cell viability, and lactate levels.

DISCUSSION: This study fills the gap in the application of traditional Chinese medicine to HIPEC, providing a solid theoretical foundation for the advancement of traditional Chinese medicine.

CONCLUSION

SKDI enhances the efficacy of HIPEC for colorectal peritoneal metastatic cancer by targeting the HIF-1α-mediated glycolytic pathway, while mitigating the toxic side effects of HIPEC. The future direction of this study is to screen for the active components of drugs and conduct more in-depth investigations into their mechanisms.