The protective effect of cannabinoids against colorectal cancer cachexia through modulation of inflammation and immune responses

Biomed Pharmacother. 2023 May:161:114467. doi: 10.1016/j.biopha.2023.114467. Epub 2023 Mar 3.

Abstract

Cancer cachexia is a multifactorial disorder characterized by weight loss and muscle wasting, and there are currently no FDA-approved medications. In the present study, upregulation of six cytokines was observed in serum samples from patients with colorectal cancer (CRC) and in mouse models. A negative correlation between the levels of the six cytokines and body mass index in CRC patients was seen. Gene Ontology analysis revealed that these cytokines were involved in regulating T cell proliferation. The infiltration of CD8+ T cells was found to be associated with muscle atrophy in mice with CRC. Adoptive transfer of CD8+ T cells isolated from CRC mice resulted in muscle wasting in recipients. The Genotype-Tissue Expression database showed that negative correlations between the expression of cachexia markers and cannabinoid receptor 2 (CB2) in human skeletal muscle tissues. Pharmacological treatment with Δ9-tetrahydrocannabinol (Δ9-THC), a selective CB2 agonist or overexpression of CB2 attenuated CRC-associated muscle atrophy. In contrast, knockout of CB2 with a CRISPR/Cas9-based strategy or depletion of CD8+ T cells in CRC mice abolished the Δ9-THC-mediated effects. This study demonstrates that cannabinoids ameliorate CD8+ T cell infiltration in CRC-associated skeletal muscle atrophy via a CB2-mediated pathway. Serum levels of the six-cytokine signature might serve as a potential biomarker to detect the therapeutic effects of cannabinoids in CRC-associated cachexia.

Keywords: CD8(+) T cell; Cannabinoid receptor 2; Cannabinoids; Colorectal cancer cachexia; Cytokines.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Cachexia / drug therapy
  • Cachexia / etiology
  • Cachexia / prevention & control
  • Cannabinoids* / pharmacology
  • Cannabinoids* / therapeutic use
  • Colorectal Neoplasms* / complications
  • Colorectal Neoplasms* / drug therapy
  • Cytokines
  • Dronabinol / pharmacology
  • Dronabinol / therapeutic use
  • Humans
  • Immunity
  • Inflammation
  • Mice
  • Muscular Atrophy

Substances

  • Cannabinoids
  • Dronabinol
  • Cytokines