Low-dose Naltrexone Inhibits Colorectal Cancer Progression and Promotes Apoptosis by Increasing M1-type Macrophages and Activating the Bax/Bcl-2/caspase-3/PARP Pathway

Int Immunopharmacol. 2020 Jun;83:106388. doi: 10.1016/j.intimp.2020.106388. Epub 2020 Mar 11.

Abstract

The incidence of colorectal cancer (CRC) is increasing annually worldwide. However, traditional chemotherapy has obvious side effects. Low-dose naltrexone (LDN) has been reported to delay tumor progression, but the mechanism remains unclear. Therefore, the aim of this study was to explore the mechanisms underlying the inhibitory effect of LDN on CRC progression in vivo and in vitro. We found that expression of macrophage markers (F4/80, CD68) was increased in nude mice treated with LDN compared with the control group (p < 0.05). Additionally, levels of M1 macrophage phenotypic markers (CD80) and cytokines (tumor necrosis factor-α, TNF-α) were higher than in the control group (p < 0.05). LDN was able to upregulate expression of the opioid growth factor receptor (OGFr) and apoptosis-related factors Bax, caspase-9, caspase-3, and PARP and downregulate expression of Bcl-2, Survivin, and Ki67 to promote tumor cell apoptosis. Therefore, we speculate that LDN reduces tumor size by increasing levels of M1-like macrophages and activating the Bax/Bcl-2/caspase-3/PARP signaling pathway to induce apoptosis. We suggest that LDN has potential for the treatment of CRC.

Keywords: Apoptosis; Bax/Bcl-2/caspase-3/PARP; Colorectal cancer (CRC) progression; Low-dose naltrexone (LDN); M1-like macrophages; Opioid growth factor receptor (OGFr).