Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer
Version of Record online: 5 SEP 2014
© 2014 The British Pharmacological Society
British Journal of Pharmacology
Volume 171, Issue 19, pages 4464–4477, October 2014
How to Cite
Murase, R., Kawamura, R., Singer, E., Pakdel, A., Sarma, P., Judkins, J., Elwakeel, E., Dayal, S., Martinez-Martinez, E., Amere, M., Gujjar, R., Mahadevan, A., Desprez, P.-Y. and McAllister, S. D. (2014), Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer. British Journal of Pharmacology, 171: 4464–4477. doi: 10.1111/bph.12803
- Issue online: 23 SEP 2014
- Version of Record online: 5 SEP 2014
- Accepted manuscript online: 9 JUN 2014 04:58AM EST
- Manuscript Accepted: 20 MAY 2014
- Manuscript Revised: 29 APR 2014
- Manuscript Received: 13 DEC 2013
- National Institutes of Health. Grant Numbers: CA082548, CA135281, DA009789, DA005488
- California Breast Cancer Research Program. Grant Number: 12IB-0116
- Komen Breast Cancer Research Foundation. Grant Number: KG090385
Background and Purpose
The psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways.
To measure breast cancer cell proliferation/viability and invasion, MTT and Boyden chamber assays were used. Modulation of reactive oxygen species (ROS) and apoptosis was measured using dichlorodihydrofluorescein and annexin/propidium iodide, respectively, in combination with cell flow cytometry. Changes in protein levels were evaluated using Western analysis. Orthotopic and i.v. mouse models of breast cancer metastasis were used to test the activity of cannabinoids in vivo.
CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. However, this was associated with moderate increases in survival. We therefore screened for analogues that could co-target cannabinoid anti-tumour pathways (CBD- and THC-associated) and discovered the compound O-1663. This analogue inhibited Id1, produced a marked stimulation of ROS, up-regulated autophagy and induced apoptosis. Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo.
Conclusions and Implications
O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer.