Photoactivated full-API nanodrug (FAND): harnessing transition metal complexes and MTH1 inhibitor for enhanced DNA damage in cancer cells.

The effectiveness of photodynamic therapy (PDT) has been greatly restricted by the hypoxic tumor microenvironment and the susceptible resistance of monotherapy. Although nanodrugs based on transition metal complexes capable of integrating PDT with photoactivated chemotherapy (PACT) have garnered tremendous attention as promising candidates for overcoming the above limitations, the therapeutic efficacy of these nanodrugs is still hampered by inadequate loading of active pharmaceutical ingredients (APIs) and the inherent ability of cancer cells to repair damaged DNA. Herein, we developed a photoactivated full-API nanodrug, Ru-T FAND, by one-step self-assembly of RuDPB and TH287. By virtue of its 100 wt% API content and favorable stability in water, the Ru-T FAND exhibited improved cellular uptake behavior and intracellular 1O2 generation. Attractively, the Ru-T FAND with triple anti-cancer modalities can photogenerate 1O2, photo-release DPB ligand and inhibit the repair of DNA damage, ultimately enhancing its phototherapeutic effect on cancer cells. Importantly, the uncaged DPB ligand from RuDPB emits red fluorescence, enabling real-time monitoring of the drug's absorption, distribution and efficacy. Collectively, the presented photoactivated Ru-T FANDs with multiple anti-cancer mechanisms will expand new horizons for the development of safe, efficient and synergistic tumor phototherapy strategies.

BMP9 mediates the anticancer activity of evodiamine through HIF­1α/p53 in human colon cancer cells.

Colon cancer is one of the most common malignancies. Although there has been great development in treatment regimens over the last few decades, its prognosis remains poor. There is still a clinical need to find new drugs for colon cancer. Evodiamine (Evo) is a quinolone alkaloid extracted from the traditional herbal medicine plant Evodia rutaecarpa. In the present study, CCK­8, flow cytometry, reverse transcription quantitative polymerase chain reaction, western blot analysis and a xenograft tumor model were used to evaluate the anti­cancer activity of Evo in human colon cancer cells and determine the possible mechanism underlying this process. It was revealed that Evo exhibited prominent anti­proliferation and apoptosis­inducing effects in HCT116 cells. Bone morphogenetic protein 9 (BMP9) was notably upregulated by Evo in HCT116 cells. Exogenous BMP9 potentiated the anti­cancer activity of Evo, and BMP9 silencing reduced this effect. In addition, HIF­1α was also upregulated by Evo. The anticancer activity of Evo was enhanced by HIF­1α, but was reduced by HIF­1α silencing. BMP9 potentiated the effect of Evo on the upregulation of HIF­1α, and enhanced the antitumor effect of Evo in colon cancer, which was clearly reduced by HIF­1α silencing. In HCT116 cells, Evo increased the phosphorylation of p53, which was enhanced by BMP9 but reduced by BMP9 silencing. Furthermore, the effect of Evo on p53 was potentiated by HIF­1α and reduced by HIF­1α silencing. The present findings therefore strongly indicated that the anticancer activity of Evo may be partly mediated by BMP9 upregulation, which can activate p53 through upregulation of HIF­1α, at least in human colon cancer.