An artesunate-modified half-sandwich iridium(iii) complex inhibits colon cancer cell proliferation and metastasis...

Area of Science:

• Oncology
• Medicinal Chemistry
• Cancer Biology

Background:

• Colon cancer is a prevalent and aggressive digestive system malignancy.
• Aberrant Signal Transducer and Activator of Transcription 3 (STAT3) activation drives tumor proliferation, metastasis, and immune evasion.
• Targeting the STAT3 pathway is a promising strategy for colon cancer therapy.

Purpose of the Study:

• To synthesize and evaluate a novel iridium complex, Ir-ART, for its efficacy against colon cancer.
• To investigate the mechanism of action of Ir-ART in inhibiting colon cancer cell growth and metastasis.
• To assess the potential of Ir-ART in initiating antitumor immune responses.

Main Methods:

• Synthesis of the half-sandwich iridium complex Ir-ART.
• Assessment of antiproliferative activity against human colon cancer HCT-116 cells.
• Mechanistic studies involving cellular localization, protein expression analysis (STAT3, γ-H2AX, cyclin B1), reactive oxygen species (ROS) generation, mitochondrial membrane potential, and metalloproteinase 9 (MMP-9) and cyclooxygenase-2 (COX-2) downregulation.
• Evaluation of immunogenic cell death induction.

Main Results:

• Ir-ART demonstrated significant antiproliferative effects on HCT-116 cells.
• The complex reduced STAT3 protein expression in a dose-dependent manner.
• Ir-ART localized in the nucleus and mitochondria, inducing DNA damage (γ-H2AX reduction), cell cycle arrest (cyclin B1 reduction), ROS accumulation, and mitochondrial dysfunction, leading to autophagic cell death.
• Cancer cell migration was inhibited via MMP-9 downregulation.
• Ir-ART promoted antitumor immunity by inducing immunogenic cell death and reducing the immunosuppressive cytokine COX-2.

Conclusions:

• Ir-ART effectively suppresses colon cancer proliferation and metastasis through multiple mechanisms, including STAT3 inhibition and induction of autophagic cell death.
• The complex exhibits potential for dual application in colon cancer chemotherapy and immunotherapy.
• Ir-ART represents a promising candidate for further development in colon cancer treatment strategies.