Synthesis and biological evaluation of α-D-tocopherol derivatives as anticancer agents targeting mitochondrial...

Area of Science:

• Biochemistry
• Oncology
• Mitochondrial Biology

Background:

• Gastric cancer (GC) has a poor prognosis, largely due to cancer stem cells (CSCs).
• The aggressive stem-like/EMT/Mesenchymal (SEM) GC subtype, enriched in CSCs, relies on mitochondrial complex II (CII) for survival and exhibits resistance to chemotherapy.
• Targeting metabolic vulnerabilities, such as CII respiration in CSCs, presents a potential therapeutic avenue.

Purpose of the Study:

• To explore novel α-D-tocopherol derivatives as targeted therapies for GC, specifically focusing on inhibiting succinate dehydrogenase (SDH), the catalytic core of CII.
• To evaluate the efficacy of these derivatives against GC cells with enriched cancer stemness (S-cells) and in patient-derived organoid (PDO) models of SEM-type GC.
• To elucidate the mechanism of action, including effects on SDH activity, oxygen consumption, reactive oxygen species (ROS) production, and apoptosis.

Main Methods:

• Synthesis and evaluation of α-D-tocopherol derivatives (malonate derivative 10 and primary amide derivative 17).
• In vitro assays to determine anti-proliferative activity (GI50 values) in S-cells and GC PDOs, and to assess SDHC activity and oxygen consumption rates (OCR).
• In vivo studies using xenograft models to evaluate tumor growth inhibition and systemic toxicity.

Main Results:

• Derivatives 10 and 17 demonstrated potent anti-proliferative activity against S-cells, significantly outperforming α-TOS.
• Mechanistic studies confirmed that derivatives 10 and 17 inhibit SDHC activity, reduce CII-specific OCR, increase ROS production, and induce apoptosis.
• In SEM-type GC PDOs (SDHC-high), derivatives 10 and 17 showed enhanced anti-proliferative effects compared to non-SEM-type PDOs (SDHC-low) and α-TOS.
• In vivo, compound 10 significantly inhibited tumor growth in xenograft models with minimal toxicity.

Conclusions:

• α-D-tocopherol derivatives 10 and 17 selectively target SDHC, disrupting mitochondrial complex II function and redox homeostasis.
• These derivatives induce apoptosis and exhibit significant anti-tumor efficacy against SEM-type gastric cancer in vitro and in vivo.
• Targeting SDHC represents a promising strategy for developing novel therapeutics against aggressive, stem-like gastric cancer.