Cyclometalated iridium(III) complexes as anti-breast cancer and anti-metastasis agents via STAT3 inhibition

Abstract

Breast cancer is the most commonly diagnosed cancer and second‑leading cause of cancer deaths in women. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting breast cancer cell proliferation, invasion, angiogenesis, and metastasis, and the high expression of STAT3 is related to the occurrence and poor chemotherapy sensitivity of breast cancer. Iridium(III) complexes Ir-PTS-1– 4 containing a pterostilbene-derived ligand were synthesized to inhibit the STAT3 pathway in breast cancer. Ir-PTS-4 inhibited the proliferation of breast cancer cells by suppressing the expression of phosphorylated STAT3 and STAT3-related cyclin D1, arresting cell cycle in the S-phase, inducing DNA damage and reactive oxygen species (ROS) generation, eventually leading to autophagic cell death. The cell metastasis and invasion were also inhibited after Ir-PTS-4 treatment. Besides, Ir-PTS-4 exhibited excellent anti-proliferation activity in 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work presents the rational design of metal-based anticancer agents to block the STAT3 pathway for simultaneously inhibiting breast cancer proliferation and metastasis.