SH003 Inhibits Proliferation and Induces Apoptosis in Colon Cancer Through the RTK-STAT3 Pathway

Abstract

Background/aim: Colon cancer is the most prevalent type of gastrointestinal cancer, characterized by high incidence and mortality rates despite advancements in diagnosis and treatment. Although chemotherapy is the standard treatment for advanced cases, survival benefits are often limited, highlighting the need for innovative therapeutic strategies. SH003, an herbal mixture composed of Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, has demonstrated anticancer properties across various cancer types. This study aimed to explore the anticancer effects of SH003 on colon cancer through in vitro and in vivo experiments.

Materials and methods: In vitro studies were conducted using human colon cancer cell lines, including HCT116, HT29, SW480, SW620, LoVo, LS174T, H508, and LS1034. Cell viability assays were performed to determine IC₅₀ values over time. Apoptosis induction was assessed through Western blot analysis. Cell cycle progression was analyzed by examining the expression of cell cycle-related proteins. The disruption of the RTK-STAT3 signaling pathway was evaluated by measuring the phosphorylation of ALK using RTK-array. In vivo experiments involved establishing an HCT116 xenograft mouse model to assess tumor growth inhibition and systemic toxicity following SH003 administration.

Results: SH003 significantly reduced cell viability in all tested colon cancer cell lines, with IC₅₀ values decreasing over time, indicating a time-dependent cytotoxic effect. Apoptosis induction was confirmed by increased levels of cleaved PARP, caspase-3, caspase-8, and caspase-9. SH003 also induced G₁/S phase cell cycle arrest, as evidenced by decreased expression of p-Rb, CDK2, CDK4, and Cyclin D1. Furthermore, SH003 disrupted the RTK-STAT3 signaling pathway by reducing ALK phosphorylation and decreasing the levels of p-STAT3, c-Myc, and cyclin D1. In vivo, SH003 significantly suppressed tumor growth in the HCT116 xenograft mouse model, reducing tumor volumes without causing notable systemic toxicity.

Conclusion: These findings suggest that SH003 possesses robust anticancer effects against colon cancer by inducing apoptosis, causing cell cycle arrest, and disrupting RTK-STAT3 signaling. The in vivo results further confirm SH003's efficacy and safety, supporting its potential as a promising therapeutic option for colon cancer treatment. Further studies are warranted to elucidate its mechanisms and clinical applicability.

Keywords: RTK/STAT3 signaling pathway; SH003; apoptosis; colon cancer.