The CB1 Blocker Rimonabant Slowed Colon Cancer Growth by Disrupting a Key Cancer-Promoting Pathway | Research

The takeaway

The CB1 inverse agonist rimonabant inhibited the Wnt/beta-catenin pathway in aggressive colon cancer cells and significantly reduced tumor growth in mice, suggesting cannabinoid receptor modulation could play a role in cancer therapy.

Readers interested in cannabinoid receptors and cancer biology.

Rimonabant significantly reduced colon cancer tumor growth in mice by blocking the Wnt/beta-catenin pathway

What the researchers found

Researchers tested rimonabant, a CB1 receptor inverse agonist, on two colon cancer cell lines carrying mutations associated with metastatic cancer that responds poorly to chemotherapy.

Rimonabant inhibited the Wnt/beta-catenin signaling pathway, one of the most important cancer-promoting pathways in colorectal cancer, and increased the phosphorylation (deactivation) of beta-catenin. In one cell line (HCT116), it also activated a non-canonical Wnt pathway through Wnt5A and CaMKII. Part of rimonabant's mechanism involved directly inhibiting the p300/KAT3B histone acetyltransferase, an enzyme that helps activate cancer-promoting genes.

In living mice with HCT116 tumor xenografts, rimonabant significantly reduced tumor growth and disrupted the nuclear localization of beta-catenin (the protein must be in the nucleus to drive cancer gene expression).

Why it matters

Colorectal cancer with activated Wnt/beta-catenin signaling (present in over 85% of cases) is particularly difficult to treat with existing chemotherapy. Rimonabant's ability to inhibit this pathway through a novel mechanism, cannabinoid receptor modulation combined with direct epigenetic enzyme inhibition, opens a new therapeutic angle.

The numbers in context

Over 85% of colorectal cancers involve APC/Wnt/beta-catenin pathway activation. Two cell lines tested (HCT116, SW48). Rimonabant significantly reduced xenograft tumor growth in vivo. p300/KAT3B histone acetyltransferase was directly inhibited.

How the study worked

In vitro experiments on HCT116 and SW48 colon cancer cell lines examined rimonabant's effects on the Wnt/beta-catenin pathway. Histone acetyltransferase activity assays tested direct enzyme inhibition. In vivo experiments used HCT116 xenografts in mice to assess tumor growth effects.

What this study cannot tell us

Rimonabant was withdrawn from the European market in 2008 due to psychiatric side effects (depression, suicidal ideation) when used as an anti-obesity drug. Its use as a cancer therapy would require careful risk-benefit assessment. The cell lines and xenograft model may not fully represent human colon cancer biology. The study examined only two specific genetic profiles of colorectal cancer.

How to read the evidence

Preliminary evidence from cell culture and animal experiments. No human clinical data for this cancer application.

When this study was published

Published in 2017. Note that rimonabant was previously withdrawn from the obesity market due to psychiatric side effects.

The bigger picture

The relationship between the endocannabinoid system and cancer is complex. While some cannabinoids promote cancer cell death, others may stimulate growth depending on the receptor, cell type, and context. This study specifically demonstrates that blocking (rather than activating) the CB1 receptor can inhibit cancer growth in certain genetic backgrounds, adding nuance to the cannabinoid-cancer narrative.

Questions still open

Could rimonabant or safer CB1 inverse agonists be used in combination with standard chemotherapy? Would the psychiatric side effects limit cancer treatment duration? Do other cannabinoid receptor modulators show similar anti-cancer effects through the Wnt pathway?

Common questions

Does this mean cannabinoids can treat cancer?

This study used a CB1 receptor blocker (the opposite of THC's action), not a cannabinoid agonist. It found that blocking CB1 receptors inhibited a cancer pathway in colon cancer cells and reduced tumor growth in mice. This is preclinical evidence and does not mean cannabinoids or their blockers are established cancer treatments.

Why was rimonabant taken off the market?

Rimonabant was approved in Europe as an anti-obesity drug but was withdrawn in 2008 due to serious psychiatric side effects including depression and suicidal thoughts. It was never approved in the United States. Its potential use in cancer would be a different context with different risk-benefit calculations.

Read the original research

Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer.

Scientific reports, 7(1), 11678

View on PubMed ↗Publisher’s paper ↗

Citation

Proto, Maria Chiara; Fiore, Donatella; Piscopo, Chiara; Franceschelli, Silvia; Bizzarro, Valentina; Laezza, Chiara; Lauro, Gianluigi; Feoli, Alessandra; Tosco, Alessandra; Bifulco, Giuseppe; Sbardella, Gianluca; Bifulco, Maurizio; Gazzerro, Patrizia. (2017). Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer.. Scientific reports, 7(1), 11678. https://doi.org/10.1038/s41598-017-11688-x