Modulating cancer cell survival by targeting intracellular cholesterol transport

Area of Science:

• Oncology
• Biochemistry
• Pharmacology

Background:

• Cancer cells exhibit high cholesterol demand, presenting a vulnerability for therapeutic targeting of cholesterol homeostasis.
• Disrupting intracellular cholesterol transport, similar to Niemann-Pick disease caused by acid sphingomyelinase (ASM) deficiency, is a potential anti-cancer strategy.
• Lysosomotropic compounds known as functional ASM inhibitors (FIASMAs) may possess chemotherapeutic activity by interfering with cancer cell cholesterol metabolism.

Purpose of the Study:

• To investigate the chemotherapeutic potential of inhibiting acid sphingomyelinase (ASM).
• To evaluate the effects of functional ASM inhibitors (FIASMAs) on cancer cell cholesterol levels, homeostasis, endocytosis, and signaling.
• To assess the in vivo efficacy of ASM inhibition and develop improved delivery methods.

Main Methods:

• Investigated the impact of FIASMAs on intracellular cholesterol, cellular endocytosis, and signaling pathways.
• Assessed the in vivo efficacy of ASM inhibition using melanoma xenografts.
• Developed a nanoparticle formulation to mitigate dose-limiting central nervous system (CNS) side effects associated with certain FIASMAs.

Main Results:

• Functional ASM inhibitors disrupted intracellular cholesterol transport, leading to impaired autophagic flux, endocytosis, and receptor tyrosine kinase signaling.
• Oncogenic signaling pathways crucial for cancer cell survival were inhibited by ASM inhibitors.
• Perphenazine and fluphenazine, known antipsychotics, demonstrated efficacy in inhibiting xenografted tumor growth; nanoliposomal perphenazine improved efficacy and reduced CNS side effects.

Conclusions:

• Targeting acid sphingomyelinase (ASM) to disrupt intracellular cholesterol transport represents a viable chemotherapeutic approach for cancer treatment.
• The study validates ASM inhibition as a potential strategy to combat cancer by exploiting cholesterol homeostasis vulnerabilities.