Abstract
Simple SummaryCancer cells frequently have an altered metabolism to support their increased proliferative and invasive activity. Perhexiline, a drug used to treat some cardiovascular diseases, inhibits some of the reported changes in the metabolism of cancer cells. We show that treatment with this drug either as a racemate or its enantiomers can kill colorectal cancer cells. The drug has been used clinically for a long time and has potential to be repurposed for use in the management of colorectal cancer.Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Perhexiline, a prophylactic anti-anginal drug, has been reported to have anti-tumour effects both in vitro and in vivo. Perhexiline as used clinically is a 50:50 racemic mixture ((R)-P) of (−) and (+) enantiomers. It is not known if the enantiomers differ in terms of their effects on cancer. In this study, we examined the cytotoxic capacity of perhexiline and its enantiomers ((−)-P and (+)-P) on CRC cell lines, grown as monolayers or spheroids, and patient-derived organoids. Treatment of CRC cell lines with (R)-P, (−)-P or (+)-P reduced cell viability, with IC50 values of ~4 µM. Treatment was associated with an increase in annexin V staining and caspase 3/7 activation, indicating apoptosis induction. Caspase 3/7 activation and loss of structural integrity were also observed in CRC cell lines grown as spheroids. Drug treatment at clinically relevant concentrations significantly reduced the viability of patient-derived CRC organoids. Given these in vitro findings, perhexiline, as a racemic mixture or its enantiomers, warrants further investigation as a repurposed drug for use in the management of CRC.
Highlights
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide, and is a leading cause of cancer-related death [1]
Effect of Perhexiline and Its Enatiomers on CRC Monolayer Growth. To determine their ability to inhibit cell growth, CRC cell lines and human foreskin fibroblasts (HFF) were exposed to a range of concentrations of (−)-P, (+)-P and (R)-P, and the growth of the adherent monolayer was measured by crystal violet staining
Our results show that each of the compounds significantly reduced the growth of CRC cell lines at similar concentrations, with complete inhibition observed with 8 μM
Summary
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide, and is a leading cause of cancer-related death [1]. Despite improvements in prevention and treatment strategies, the global burden of CRC is anticipated to rise by 60% with 2.2 million new cases and 1.1 million deaths annually by 2030 [2]. Alterations in metabolism are common in cancer cells, providing the increased energy and materials for functions characteristic of cancer, such as unlimited proliferation, tissue invasion and metastasis. One of the many metabolic changes reported in cancer cells is in the biosynthesis and oxidation of fatty acids. Fatty acid oxidation (FAO) results in the production of ATP and NADPH. In many cancers FAO is the major source of ATP for tumour growth, and NADPH helps protect cancer cells against oxidative stress and cell death. Alterations in FAO are an important change in cancer metabolism
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