Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy

Abstract

Abstract. 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.

Naltrexone Inhibits IL-6 and TNFα Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors

“…In this context, it is important to note that previous studies in inflammatory diseases and cancer have adopted an LDN regime as opposed to the dosages used in the treatment of opioid and alcohol dependency. Nanomolar, but not micromolar, doses of naltrexone were previously seen in studies by Liu et al to result in upregulation of pro-apoptotic genes, rendering tumor cells more susceptible to chemotherapy (46). It may, therefore, be necessary to identify suitable dosage regimes to obtain optimal therapeutic effects on individual target pathways in different diseases.…”

The efficacy of chemotherapeutic drug combinations may be predicted by concordance of gene response to the single agents

“…Data pertaining to certain genes from cells treated with gemcitabine has been published in our previous papers ( 5 , 7 ). Data pertaining to naltrexone has been published previously ( 30 ).…”

Impact of Opioid Use in Hematological Malignancies: Clinical, Immunological and Concomitant Aspects

“…LDN’s ability to suppress opioid growth factor (OGF) activity, the inhibitory growth factor that stimulates p16 and/or p21 cyclin-dependent inhibitory kinases to slow cell replication, has been proven to be effective in a number of malignant tumors, including non-small cell lung cancer (NSCLC) [ 62 ], adenoid cystic carcinoma [ 63 ], ovarian cancer [ 64 ] and B-cell lymphoma [ 65 ]. LDN affects inter-cell signaling and cell cycle regulation and reduces tumor growth by blocking opioid growth factor receptors (OGFrs) and upregulating serum enkephalin levels [ 66 ]. Additionally, cancer cells previously exposed to LDN tend to be more sensitive to chemotherapeutic agents [ 61 ].…”