Ligustrazine-Derived Chalcones-Modified Platinum(IV) Complexes Intervene in Cisplatin Resistance in Pancreatic Cancer through Ferroptosis and Apoptosis

Abstract

Developing multitarget platinum­(IV) prodrugs is an important strategy to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity. Herein, six novel ligustrazine-derived chalcones-modified platinum­(IV) complexes were synthesized and evaluated for their anti-proliferative activities. Among them, 16a displayed higher cytotoxicity toward the tested cancer cell lines and lower cytotoxicity toward the human normal cells than CDDP or the combined group. Mechanistic studies revealed that 16a efficiently induced DNA damage and initiated a mitochondria-dependent apoptosis pathway. Besides, 16a significantly triggered ferroptosis by down-regulating expression levels of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11. Further, 16a obtained superior in vivo anti-tumor efficiency than CDDP in CDDP-resistant pancreatic cancer xenograft models but showed no significant side effects. In summary, our study suggested that 16a acts via a different anti-cancer mechanistic pathway than CDDP and may therefore encompass a novel practical strategy for cancer treatment.

Natural Products–Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry

“…In addition, 66 regulates the expression level of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11 expression level, significantly induced iron sag. Furthermore, in pancreatic cancer anti-CDDP xenotransplantation models, 66 achieved better antitumor efficiency in vivo than CDDP, but without significant side effects [92].…”

Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance

“…More importantly, the two axial ligands introduced in platinum(IV) complexes could be used to promote tumor-targeting ability or bioavailability and enhance cellular uptake, respectively. , Therefore, multifunctional platinum(IV) complexes are an effective strategy to enhance antitumor efficacy, overcome the drug resistance, and reduce the side effects of the conventional platinum(II)-based drugs because of the different mechanism of antitumor action. For example, multifunctional platinum(IV) complexes (Figure ), such as CX-4945-platinum(IV), chalcone-platinum(IV), , chlorambucil-platinum(IV), BBI-608-platinum(IV), pterostilbene-platinum(IV), evodiamine-platinum(IV), fenofibric acid-platinum(IV), ketoprofen-platinum(IV), PARPis-platinum(IV), and so on, not only displayed stronger antitumor activity than that of cisplatin both in vitro and in vivo but also exhibited low toxicity toward normal tissue in cisplatin-sensitive or -resistant tumor xenograft models. Therefore, exploring a multifunctional platinum(IV) prodrug with liver-targeting ability is an ideal strategy for the development of potential anti-HCC drugs.…”