2. Academic Validation
  3. Verteporfin induces lipid peroxidation and ferroptosis in pancreatic cancer cells

Verteporfin induces lipid peroxidation and ferroptosis in pancreatic cancer cells

  • Free Radic Biol Med. 2024 Jan 4:S0891-5849(24)00003-0. doi: 10.1016/j.freeradbiomed.2024.01.003.
Wei Zhou 1,  Adrian Lim 2,  Omer Elmadbouh 2,  Mouad Edderkaoui 2,  Arsen Osipov 2,  Angela Mathison 3,  Raul Urrutia 4,  Tao Liu 5,  Qiang Wang 6,  Stephen J Pandol 7
Affiliations

Affiliations

  • 1 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • 3 Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA; Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
  • 4 Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA; Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA; Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
  • 5 Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Electronic address: [email protected].
  • 7 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Electronic address: [email protected].
PMID: 38184120 DOI: 10.1016/j.freeradbiomed.2024.01.003
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has extremely poor prognosis, with a 5-year survival rate of approximately 11 %. Yes-associated protein (YAP) is a major downstream effector of the Hippo-YAP pathway and plays a pivotal role in regulation of cell proliferation and organ regeneration and tumorigenesis. Activation of YAP signaling has been associated with PDAC progression and drug resistance. Verteporfin (VP) is a photosensitizer used for photodynamic therapy and previous work showed that it can function as a YAP Inhibitor. The efficacy of VP on human Cancer are being tested in several trials. In this study, we examined the effect of VP on Reactive Oxygen Species (ROS) and lipid peroxidation in pancreatic Cancer cells, by using fluorescent molecular probes and by measuring the levels of malondialdehyde, a metabolic byproduct and marker of lipid peroxidation. We found that VP causes rapid increase of both overall ROS and lipid peroxide levels, independent of LIGHT activation. These effects were not dependent on YAP, as knockdown of YAP did not cause ROS or lipid peroxidation or enhance VP-induced ROS production. Temoporfin, another photodynamic drug, did not show similar activities. In addition, VP treatment led to loss of cell membrane integrity and reduction of viability. Notably, the activity of VP to induce lipid peroxidation was neutralized by Ferroptosis inhibitors ferrostatin-1 or liproxstatin-1. VP treatment also reduced the levels of Glutathione Peroxidase 4 (GPX4), an Enzyme that protects against lipid peroxidation. These results indicate that VP can induce lipid peroxidation and Ferroptosis in the absence of LIGHT activation. Our findings reveal a novel mechanism by which VP inhibits tumor growth and provide insights into development of new therapeutic strategies for the treatment of pancreatic Cancer.

Keywords

Ferroptosis; Lipid peroxidation; Pancreatic cancer; Reactive oxygen species; Verteporfin.

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