Modulating cancer cell survival by targeting intracellular cholesterol transport

Omer Kuzu, Raghavendra Gowda, Mohammad A. Noory, Gavin P. Robertson

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis.Methods: Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome dose-limiting CNS-associated side effects of certain FIASMAs.Results: Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects.Conclusions: This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.

Original languageEnglish
Pages (from-to)513-524
Number of pages12
JournalBritish Journal of Cancer
Volume117
Issue number4
DOIs
Publication statusPublished - 8 Aug 2017
Externally publishedYes

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Keywords

  • ASM inhibitors
  • autophagy
  • cholesterol transport inhibitors
  • functional acid sphingomyelinase inhibitors
  • lysosomotropism
  • melanoma
  • SMPD1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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