Related Experiment Video
Updated: Jan 8, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Diphenyl Disulfide Exerts Dual Cytotoxic Effects by Inducing Ferroptosis and Apoptosis in Melanoma Cells
Sheng-Yuan Chen1,2, En-De Shu3, Jiann-Jyh Huang4
1Department of Marine Biotechnology and Research, National Sun Yat-sen University, Kaohsiung, 804, Taiwan.
Abstract:
Melanoma is a highly aggressive and heterogeneous form of skin cancer with limited effective treatment options. Although substantial progress has been made in immunotherapy, chemotherapy still serves as an essential alternative therapeutic strategy for many patients. Diphenyl disulfide (DPDS), a small molecule composed of two phenyl groups linked by a disulfide bond, has been reported to exert antioxidant and anticancer activities across several types of malignancies. In this study, we examined the cytotoxic effects of DPDS on melanoma cells and investigated the underlying mechanisms responsible for its antitumor activity. Our results showed that DPDS induces both ferroptosis and apoptosis in melanoma cells in a time-dependent manner. At 24 h, DPDS promoted lipid peroxidation, enhanced xCT ubiquitination, and reduced GPX4 expression, all of which are characteristic hallmarks of ferroptosis. Whereas at 48 h, apoptosis occurred, likely because of NRF2 phosphorylation inhibition, which initially protected against cell death. Additionally, DPDS inhibited the PI3K/AKT/mTOR pathway, leading to decreased mTOR expression and increased autophagy levels. Furthermore, the inhibition of ferroptosis or autophagy partially restored cell viability, suggesting a complex interplay between these pathways in DPDS-induced cytotoxicity. These findings highlight that DPDS may be a potential therapeutic agent for melanoma that functions by leveraging dual programmed cell death mechanisms and targeting the PI3K/AKT/mTOR signaling pathway.
Insights
Diphenyl disulfide (DPDS) shows potential as a melanoma treatment by inducing both ferroptosis and apoptosis. This small molecule targets key cell death pathways and the PI3K/AKT/mTOR signaling pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Melanoma is an aggressive skin cancer with limited treatment options.
- Chemotherapy remains a vital strategy for many melanoma patients.
- Diphenyl disulfide (DPDS) exhibits anticancer properties in various malignancies.
Purpose of the Study:
- To investigate the cytotoxic effects of DPDS on melanoma cells.
- To elucidate the mechanisms underlying DPDS's antitumor activity.
- To explore the role of ferroptosis, apoptosis, and autophagy in DPDS-induced cell death.
Main Methods:
- Treatment of melanoma cells with DPDS.
- Analysis of ferroptosis markers (lipid peroxidation, xCT ubiquitination, GPX4 expression).
- Assessment of apoptosis via NRF2 phosphorylation.
- Investigation of the PI3K/AKT/mTOR pathway and autophagy.
- Evaluation of cell viability after inhibiting ferroptosis or autophagy.
Main Results:
- DPDS induced time-dependent ferroptosis and apoptosis in melanoma cells.
- DPDS promoted lipid peroxidation and hallmarks of ferroptosis within 24 hours.
- Apoptosis occurred at 48 hours, linked to NRF2 phosphorylation inhibition.
- DPDS inhibited the PI3K/AKT/mTOR pathway, increasing autophagy.
- Partial restoration of cell viability upon ferroptosis or autophagy inhibition.
Conclusions:
- DPDS exhibits dual programmed cell death mechanisms (ferroptosis and apoptosis) in melanoma.
- DPDS targets the PI3K/AKT/mTOR signaling pathway, influencing autophagy.
- DPDS demonstrates potential as a therapeutic agent for melanoma.
- The interplay between ferroptosis, apoptosis, and autophagy is crucial for DPDS's cytotoxicity.
Related Concept Videos
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...