Overcoming Cancer Resistance to Platinum Drugs by Inhibiting Cholesterol Metabolism

Abstract

Drug resistance is a serious challenge for platinum anticancer drugs. Platinum complexes may get over the drug resistance via a distinct mechanism of action. Cholesterol is a key factor contributing to the drug resistance. Inhibiting cellular cholesterol synthesis and uptake provides an alternative strategy for cancer treatment. Platinum(IV) complexes FP and DFP with fenofibric acid as axial ligand(s) were designed to combat the drug resistance through regulating cholesterol metabolism besides damaging DNA. In addition to producing reactive oxygen species and active platinum(II) species to damage DNA, FP and DFP inhibited cellular cholesterol accumulation, promoted cholesterol efflux, upregulated peroxisome proliferator‐activated receptor alpha (PPARα), induced caspase‐1 activation and gasdermin D (GSDMD) cleavage, thus leading to both apoptosis and pyroptosis in cancer cells. The reduction of cholesterol significantly relieved the drug resistance of cancer cells. The double‐acting mechanism gave the complexes strong anticancer activity in vitro and vivo, particularly against cisplatin‐resistant cancer cells.

Disruption of lipid metabolism to induce ferroptosis using multifunctional fibrate-Pt(iv) prodrugs for cancer treatment

“…26 A recent study by another group also reported two Pt( iv ) compounds, FP and DFP, utilizing fenofibric acid as an axial ligand to regulate cholesterol metabolism and damage DNA, thereby addressing drug resistance. 72 These two complexes generate reactive oxygen species, induce DNA damage, inhibit cholesterol accumulation, and promote cholesterol efflux. 72 Additionally, they upregulate PPARα and activate gasdermin D (GSDMD) and caspase-1, thereby stimulating apoptosis and pyroptosis in cancer cells.…”

“…72 These two complexes generate reactive oxygen species, induce DNA damage, inhibit cholesterol accumulation, and promote cholesterol efflux. 72 Additionally, they upregulate PPARα and activate gasdermin D (GSDMD) and caspase-1, thereby stimulating apoptosis and pyroptosis in cancer cells. By reducing cholesterol levels in cancer cells, these complexes significantly alleviate drug resistance and exhibit remarkable in vitro and in vivo anticancer effects, especially in cisplatin-resistant cells.…”

“…By reducing cholesterol levels in cancer cells, these complexes significantly alleviate drug resistance and exhibit remarkable in vitro and in vivo anticancer effects, especially in cisplatin-resistant cells. 72…”

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.…”

Gemfibrozil-Platinum(IV) Precursors for New Enhanced-Starvation and Chemotherapy In Vitro and In Vivo

“…The regulation of cholesterol by activating peroxisome proliferator activating receptors (PPARs) has received extensive attention . Gemfibrozil (GFB) is a prototype activator of PPARα (an isotype of PPARs) and approved by the FDA for clinical use to lower blood lipids .…”