Targeting Ca²⁺ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Mitochondria are crucial for cellular functions like energy metabolism and apoptosis.
• Mitochondrial dysfunction is common in cancer, and homeostasis is key to chemotherapy response.
• Thioridazine (TR), an antipsychotic, shows anticancer potential in leukemia models.

Purpose of the Study:

• To investigate the mechanisms of thioridazine-induced cytotoxicity in human leukemia cells.
• To explore the role of calcium (Ca2+) and endoplasmic reticulum (ER) stress in TR's anticancer effects.
• To evaluate TR's efficacy against BCL-2/BCL-xL-overexpressing leukemia cells.

Main Methods:

• Human leukemia cell models were used for in vitro cytotoxicity assays.
• PCR array analysis was performed to assess cell death pathway gene expression.
• Mechanistic studies involved measuring cytosolic Ca2+ flux, mitochondrial uptake, and caspase activation.

Main Results:

• Thioridazine demonstrated selective cytotoxicity against human leukemia cells.
• TR induced a rapid Ca2+ pulse, followed by mitochondrial Ca2+ uptake, permeabilization, and apoptosis.
• TR-induced cell death was prevented by Ca2+ chelators, dithiothreitol, or CHOP knockdown.
• TR was effective against BCL-2/BCL-xL-overexpressing leukemia cells.

Conclusions:

• Thioridazine induces apoptosis in leukemia cells via a Ca2+-mediated pathway involving mitochondrial permeabilization and ER stress.
• TR exhibits potent cytotoxicity, suggesting its potential as an adjuvant in antitumor chemotherapy.
• TR's effectiveness against resistant leukemia cells warrants further investigation.