Antidepressants Sertraline and Indatraline Trigger Cancer Cell Death via Cholesterol

This groundbreaking study reveals how two FDA-approved antidepressants can be repurposed as cancer treatments through a novel cholesterol-dependent mechanism. Researchers at INSERM and Gustave Roussy Cancer Center discovered that sertraline (Zoloft) and indatraline disrupt cholesterol transport within cancer cells, leading to immunogenic cell death that mobilizes anti-tumor immunity.

The team used cell-based drug screening to identify compounds that activate TFEB, a master regulator of lysosomal function. Both antidepressants caused cholesterol accumulation within lysosomes by inhibiting the cholesterol transporters NPC1 and NPC2, while simultaneously upregulating their expression through TFEB activation. This created a toxic buildup that caused lysosomal membrane permeabilization and cell death that could be reversed by cholesterol depletion.

In cancer cell experiments, both drugs triggered immunogenic cell death - a special form of cell death that releases danger signals to activate immune responses. When researchers injected mice with cancer cells pre-treated with these compounds, the dying cells acted as prophylactic vaccines, providing significant protection against subsequent tumor challenges. In therapeutic settings, a single dose of either drug substantially reduced established tumor growth in a T-cell-dependent manner.

Molecular docking analysis confirmed that both compounds can directly bind to and inhibit NPC1 and NPC2 cholesterol transporters. The drugs also upregulated PLA2G15, an enzyme that further elevates lysosomal cholesterol levels, creating a multi-pronged attack on cholesterol homeostasis.

These findings open new therapeutic avenues for cancer treatment using existing medications with well-established safety profiles. The research demonstrates how targeting lysosomal cholesterol transport can convert cancer cells into immunogenic vaccines, potentially transforming how we approach cancer immunotherapy.