Lipoic acid-conjugated chalcones exert antitumor activity via ROS elevation and ferroptosis

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Drug resistance and off-target toxicity are critical challenges in cancer treatment.
• Ferroptosis, a regulated cell death pathway driven by lipid peroxidation, presents a novel therapeutic target.
• Natural chalcones show antitumor potential but lack efficacy and selectivity.

Purpose of the Study:

• To design and synthesize novel alpha-lipoic acid (LA)-conjugated chalcone derivatives.
• To investigate the potential of these conjugates to induce ferroptosis in cancer cells by disrupting redox and iron homeostasis.
• To evaluate the efficacy and selectivity of these compounds, particularly in T24 bladder cancer cells.

Main Methods:

• Synthesis of novel alpha-lipoic acid (LA)-conjugated chalcone derivatives.
• Assessment of reactive oxygen species (ROS) levels in various cancer cell lines.
• Evaluation of cell growth inhibition and migration suppression.
• Mechanistic studies using RNA-sequencing and functional assays to elucidate ferroptosis induction pathways.

Main Results:

• The synthesized LA-chalcone conjugates elevated ROS levels, most notably in T24 bladder cancer cells.
• The lead compound, CA-LA, demonstrated potent inhibition of cancer cell growth and migration.
• Mechanistic investigations confirmed that CA-LA induces ferroptosis by dysregulating cellular iron and glutathione metabolism.
• The compounds exhibited selectivity towards T24 bladder cancer cells.

Conclusions:

• Novel alpha-lipoic acid-chalcone hybrids represent a rational design strategy for redox-directed anticancer agents.
• These compounds effectively induce ferroptosis, offering a promising approach to overcome drug resistance and minimize toxicity.
• LA-chalcone hybrids show potential as selective therapeutic agents for bladder cancer treatment via ferroptosis induction.