Bufadienolides from Chansu Injection Synergistically Enhances the Antitumor Effect of Erlotinib by Inhibiting the KRAS Pathway in Pancreatic Cancer.

The Chansu injection (CSI), a sterile aqueous solution derived from Chansu, is applied in clinical settings to support antitumor and anti-radiation treatments. CSI's principal active components, bufadienolides (≥90%), demonstrate potential effects on pancreatic cancer (PDAC), but their underlying mechanisms remain unclear. This study aimed to elucidate the antitumor effects and pathways associated with CSI in PDAC. Network pharmacology and bioinformatics analyses explored CSI's mechanisms against PDAC. MTT, colony-formation, and migration assays evaluated CSI's impact on proliferation and migration in PANC-1 and MIA PACA-2 cells, both as a single agent and in combination with erlotinib (EGFR inhibitor). Cell cycle analysis employed flow cytometry. Animal experiments were performed on tumor-bearing mice, with targets and pathways assessed via molecular docking and western blotting. CSI treatment suppressed PDAC cell proliferation and migration by inducing G2/M phase arrest. Network pharmacology, bioinformatics, and molecular docking indicated that CSI's anti-PDAC effects may involve EGFR pathway modulation, with CSI lowering p-EGFR/KRAS/p-ERK1/2 pathway expressions in PDAC cells. Additionally, sustained KRAS activation in mediating erlotinib resistance in PDAC and CSI potentiated erlotinib's antitumor effects through enhanced KRAS and p-ERK1/2 inhibition. CSI also enhanced erlotinib's efficacy in tumor-bearing mice without causing detectable toxicity in renal, cardiac, or hepatic tissues at therapeutic doses. CSI as an adjuvant used in antitumor and anti-radiation therapies enhanced erlotinib's antitumor effects through modulation of the KRAS pathway. CSI and erlotinib's synergistic interaction represents a promising approach for addressing erlotinib resistance in PDAC treatment.