Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy.
It has been reported that lower doses of the opioid antagonist naltrexone are able to reduce tumour growth by interfering with cell signalling as well as by modifying the immune system. We have evaluated the gene expression profile of a cancer cell line after treatment with low-dose naltrexone (LDN), and assessed the effect that adapting treatment schedules with LDN may have on enhancing efficacy. LDN had a selective impact on genes involved with cell cycle regulation and immune modulation. Similarly, the pro-apoptotic genes BAD and BIK1 were increased only after LDN. Continuous treatment with LDN had little effect on growth in different cell lines; however, altering the treatment schedule to include a phase of culture in the absence of drug following an initial round of LDN treatment, resulted in enhanced cell killing. Furthermore, cells pre-treated with LDN were more sensitive to the cytotoxic effects of a number of common chemotherapy agents. For example, priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell killing to 49±7.0 vs. 14±2.4% in cultures where priming was not used. Interestingly, priming with NTX before oxaliplatin resulted in just 32±1.8% cell killing. Our data support further the idea that LDN possesses anticancer activity, which can be improved by modifying the treatment schedule.
Department of Oncology, Institute for Infection and Immunity, St. George's University of London, London SW17 0RE, UK.
Wai M
WM
Liu
Department of Oncology, Institute for Infection and Immunity, St. George's University of London, London SW17 0RE, UK.
Katherine A
KA
Scott
Department of Oncology, Institute for Infection and Immunity, St. George's University of London, London SW17 0RE, UK.
Jayne L
JL
Dennis
Department of Oncology, Institute for Infection and Immunity, St. George's University of London, London SW17 0RE, UK.
Elwira
E
Kaminska
Department of Oncology, Institute for Infection and Immunity, St. George's University of London, London SW17 0RE, UK.
Alan J
AJ
Levett
Department of Oncology, Institute for Infection and Immunity, St. George's University of London, London SW17 0RE, UK.
Angus G
AG
Dalgleish
D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D024101:Mitochondrial Proteins; D009271:Naltrexone / Q000008:administration & dosage*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D051025:bcl-Associated Death Protein / Q000096:biosynthesis / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C096820:BIK protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009944:Organoplatinum Compounds; D051025:bcl-Associated Death Protein; D000077150:Oxaliplatin; D009271:Naltrexone