Combination of ruthenium (II) polypyridyl complex ?-Ru1 and Taxol enhances the anti-cancer effect on Taxol-resistant cancer cells through Caspase-1/GSDMD-mediated pyroptosis

Taxol is the first-line drug for cancer treatment. However, tumor resistance to Taxol is still a significant challenge in clinical practice. Here, we studied the synergistic effect of a ruthenium (II) polypyridyl complex, delta-[Ru (bpy)(2)(HPIP)](ClO4)(2)(delta-Ru1, where bpy = 2,2 '-bipyridine, HPIP = 2-(2-hydroxyphenyl) imidazo[4,5-f] [1, 10] phenanthroline) combined with Taxol (delta-Ru1 & Taxol) on Taxol resistant cervical cancer HeLa cell line (HeLa/ Taxol). The results of the Chou-Talalay and Synergyfinder analytical test show that the delta-Ru1 & Taxol combination has a synergistic effect in HeLa/Taxol cells. Especially, vesicles structures were observed on the membranes of HeLa/Taxol cells treated with delta-Ru1 & Taxol, accompanied by cell swelling, which characterizes pyroptosis. Furthermore, the release of Interleukin-1 beta (IL-1 beta) and Lactate Dehydrogenase (LDH) were increased. At the same time, the activation and cleavage of Caspase-1 and Gasdermin D (GSDMD), the key molecules of the pyroptosis pathway, were detected. In addition, the delta-Ru1 & Taxol combination had a synergistic anti-tumor effect in the mice model and could effectively inhibit tumor growth and significantly reduce the side effects on the lungs and the neuroethology of Taxol. Taken together, the delta-Ru1 & Taxol combination can induce cell death through Caspase-1/GSDMD-mediated pyroptosis to enhance the therapeutic effect on HeLa/Taxol cells. This study provides a novel idea for the combined application of ruthenium complexes and other drugs, which may be utilized to overcome cancer drug resistance.