DHODH Inhibition Exerts Synergistic Therapeutic Effect with Cisplatin to Induce Ferroptosis in Cervical Cancer through Regulating mTOR Pathway

Abstract

Ferroptosis exhibits a potent antitumor effect and dihydroorotate dehydrogenase (DHODH) has recently been identified as a novel ferroptosis defender. However, the role of DHODH inhibition in cervical cancer cells is unclear, particularly in synergy with cisplatin via ferroptosis. Herein, shRNA and brequinar were used to knock down DHODH and directly inhibit DHODH, respectively. Immunohistochemistry and Western blotting assays were performed to measure the expression of proteins. CCK-8 and colony formation assays were employed to assess the cell viability and proliferation. Ferroptosis was monitored through flow cytometry, the malondialdehyde assay kit and JC-1 staining analyses. The nude mouse xenograft model was generated to examine the effect of combination of DHODH inhibition and cisplatin on tumor growth in vivo. The expression of DHODH was increased in cervical cancer tissues. DHODH inhibition inhibited the proliferation and promoted the ferroptosis in cervical cancer cells. A combination of DHODH inhibition and cisplatin synergistically induced both in vitro and in vivo ferroptosis and downregulated the ferroptosis defender mTOR pathway. Therefore, the combination of DHODH inhibition and cisplatin exhibits synergistic effects on ferroptosis induction via inhibiting the mTOR pathway could provide a promising way for cervical cancer therapy.

Mitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications

“…The presence of DHODH in mitochondria and its ability to neutralize lipid peroxides support its protective role against ferroptosis, and the absence of DHODH has been shown to induce ferroptosis [ 57 ]. Thus, the interference of DHODH with ferroptosis has emerged as a prospective target for treating various diseases [ 57 , 148 , 149 ].…”

Recent Progress in Ferroptosis Induced Tumor Cell Death by Anti‐tumor Metallic complexes

“…[21] Path b: inhibition of ferroptosis defender to enhance ferroptosis synergistically, such example includes the inhibition of dihydroorotate dehydrogenase (DHODH) through molecular biology tolls or specific small molecule inhibitors. [22] Oxaliplatin as another marketed drug, the mechanism of inducing ferroptosis was investigated on HT-29 cells, the inhibition of the Nrf2/HO-1 pathway and also the disruption of intracellular iron homeostasis (Elevated Fe 2 + level and human ferritin heavy chain) resulted in the downregulation of Glutathione Peroxidase 4 (GPX4) and GSH, thus leading to enhanced ROS level. [17b] In recent years, ferroptosis induced from structural novel platinum complexes has been reported (Table 1).…”

“…Path a: combination of cisplatin with immune checkpoint inhibitors (ICIs), anti‐PD1 antibodies, [18] dihydroartemisinin (DHA), [19] ursolic acid, [20] and shikonin [21] . Path b: inhibition of ferroptosis defender to enhance ferroptosis synergistically, such example includes the inhibition of dihydroorotate dehydrogenase (DHODH) through molecular biology tolls or specific small molecule inhibitors [22] …”

Narrative review of ferroptosis in obesity

“…It has been established that ferroptosis is involved in the initiation and progression of many diseases. These diseases (Figure 2) included stroke, 13 colorectal cancer, 14 hepatocellular carcinoma, 15 glaucoma, 16 oral squamous cell carcinoma, 17 traumatic brain injury, 18 acute and chronic kidney diseases, 19 cerebral ischemia–reperfusion injury, 20 spinal cord injury, 18 lung cancer, 21 gastric cancer, 22 gallbladder carcinoma, 23 cardiovascular disease, 24 thyroid cancer, 25 chronic obstructive pulmonary disease, 26 ovarian cancer, 27 cervical cancer, 28 diabetes 29,30 and nonalcoholic fatty liver disease 31 …”