Abstract

Multi-target combination therapy has emerged as a promising anti-cancer strategy. STAT3 and HDAC are key contributors to tumorigenesis and progression. We previously reported the design of a novel dual-target inhibitor of STAT3 and HDAC (named mhl-28), which was developed by employing a naturally occurring STAT3 inhibitor derived from the traditional medicinal herb Saussurea as the pharmacophore and incorporating an HDAC- inhibitory structural motif. Here, mhl-28 was shown to simultaneously inhibit STAT3 and HDAC activities, demonstrating remarkable anti-proliferation and radiosensitizing effects against various solid cancer cell lines. In vitro, mhl-28 significantly suppresses proliferation and colony formation across various solid cancer cell lines. When combined with radiotherapy, it enhanced DNA damage and micronucleus formation, increased oxidative stress and apoptosis, induced cell cycle arrest, and inhibited tumor cell migration. In vivo experiments, mhl-28 combined with radiotherapy leads to significantly greater suppression subcutaneous tumor growth in mice, demonstrating more potent antitumor and radiosensitizing effects than SAHA. These findings indicate that mhl-28, a dual-target agent derived from traditional medicine, has strong potential as an anti-tumor drug in solid tumor therapy when combined with radiation.