Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Sep 27:10:1124.
doi: 10.3389/fphar.2019.01124. eCollection 2019.

Antitumor Activity of Abnormal Cannabidiol and Its Analog O-1602 in Taxol-Resistant Preclinical Models of Breast Cancer

Andrea Tomko  1 , Lauren O'Leary  1 , Hilary Trask  1 , John C Achenbach  2 , Steven R Hall  1   3 , Kerry B Goralski  1   3 , Lee D Ellis  3 , Denis J Dupré  1
Affiliations

Antitumor Activity of Abnormal Cannabidiol and Its Analog O-1602 in Taxol-Resistant Preclinical Models of Breast Cancer

Andrea Tomko et al. Front Pharmacol. .

Abstract

Cannabinoids exhibit anti-inflammatory and antitumorigenic properties. Contrary to most cannabinoids present in the Cannabis plant, some, such as O-1602 and abnormal cannabidiol, have no or only little affinity to the CB1 or CB2 cannabinoid receptors and instead exert their effects through other receptors. Here, we investigated whether the synthetic regioisomers of cannabidiol, abnormal cannabidiol, and a closely related compound, O-1602, display antitumorigenic effects in cellular models of breast cancer and whether it could reduce tumorigenesis in vivo. Several studies have shown the effects of cannabinoids on chemotherapy-sensitive breast cancer cell lines, but less is known about the antitumorigenic effects of cannabinoids in chemotherapy-resistant cell lines. Paclitaxel-resistant MDA-MB-231 and MCF-7 breast cancer cell lines were used to study the effect of O-1602 and abnormal cannabidiol on viability, apoptosis, and migration. The effects of O-1602 and abnormal cannabidiol on cell viability were completely blocked by the combination of GPR55 and GPR18-specific siRNAs. Both O-1602 and abnormal cannabidiol decreased viability in paclitaxel-resistant breast cancer cells in a concentration-dependent manner through induction of apoptosis. The effect of these cannabinoids on tumor growth in vivo was studied in a zebrafish xenograft model. In this model, treatment with O-1602 and abnormal cannabidiol (2 µM) significantly reduced tumor growth. Our results suggest that atypical cannabinoids, like O-1602 and abnormal cannabidiol, exert antitumorigenic effects on paclitaxel-resistant breast cancer cells. Due to their lack of central sedation and psychoactive effects, these atypical cannabinoids could represent new leads for the development of additional anticancer treatments when resistance to conventional chemotherapy occurs during the treatment of breast and possibly other cancers.

Keywords: G protein–coupled receptor; apoptosis; breast cancer; cannabinoid; cell migration; paclitaxel; taxol; zebrafish.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structure of the compounds used in this study; O-1602 and abnormal cannabidiol, compared to cannabidiol.
Figure 2
Figure 2
Cell viability. (A) Effect of paclitaxel on sensitive and resistant (PR) MCF-7 and MDA-MB-231 cells. (B) Effect of O-1602 and Abn-CBD on the cell viability of MCF-10A cells. (C) Cell viability measured in paclitaxel-sensitive MCF-7 cells following 48-h treatment with various concentrations of O-1602 alone or in presence of paclitaxel. (D) Effect of Abn-CBD ± paclitaxel on taxol-sensitive MCF-7 cells. (E) Effect of O-1602 ± paclitaxel on taxol-sensitive MDA-MB-231 cells. (F) Effect of Abn-CBD ± paclitaxel on taxol-sensitive MDA-MB-231 cells.
Figure 3
Figure 3
Atypical cannabinoids effect on the viability of paclitaxel-resistant cells. (A) Cell viability measured in paclitaxel-resistant (PR) MCF-7 cells following 48-h treatment with various concentrations of O-1602 alone or in presence of paclitaxel. (B) Effect of Abn-CBD ± paclitaxel on MCF-7 PR cells. (C) Effect of O-1602 ± paclitaxel on MDA-MB-231 PR cells. (D) Effect of Abn-CBD ± paclitaxel on MDA-MB-231 PR cells.
Figure 4
Figure 4
Receptor dependence of effect on cell viability. (A) Effect of the GPR55-, GPR18-specific small interfering RNAs (siRNAs), or combination of siRNAs for both targets on cell viability in (B) MDA-MB-231 PR cells and (B) MCF-7 PR cells. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 5
Figure 5
Effect of atypical cannabinoids on apoptosis. Cells were treated for 24 h with either the DMSO vehicle, O-1602, or Abn-CBD. (A) Histogram showing the % of annexin V–labeled cells. Cells staining for PI only or both PI/AV are not shown. Cells were counted from three random fields of view on a fluorescence microscope. *p < 0.05, **p < 0.01, n = 3. (B) Western blotting analysis was performed using an anti–caspase-3 antibody, and β-tubulin was included as a loading control. Figure is a representative blot of n = 3 experiments. (C) Reactive oxygen species assay measurements in MDA-MB-231 and MCF-7 cells following treatment with O-1602 or Abn-CBD. (n = 3).
Figure 6
Figure 6
Effect of atypical cannabinoids on EGF-mediated migration and invasion. (A) Histogram summarizing Transwell migration results using MDA-MB-231 PR cells in response to EGF in presence of either the vehicle control or various concentrations of O-1602 or Abn-CBD. (B) Histogram summarizing Matrigel invasion using MDA-MB-231 PR cells in presence of either the vehicle control, O-1602, or Abn-CBD. Results represent the means ± SEM of at least three independent experiments. *p < 0.05, **p < 0.01.
Figure 7
Figure 7
Toxicity of atypical cannabinoids in zebrafish. Graph showing the percentage of zebrafish larvae affected by various concentrations of O-1602 or Abn-CBD in water for 3 days.
Figure 8
Figure 8
Effect of atypical cannabinoids on the viability of Paclitaxel-resistant breast cancer cells in vivo. (A) Images of representative zebrafish injected with human MDA-MB-231 PR cells in the yolk sac (white pixels) before (0 hpf) and following 3-day treatment with the DMSO vehicle control, O-1602, or Abn-CBD (72 hpf). (B) Quantification of the analysis of more than 24 images for each condition. ***p < 0.001.
See this image and copyright information in PMC

References

    1. Andradas C., Blasco-Benito S., Castillo-Lluva S., Dillenburg-Pilla P., Diez-Alarcia R., Juanes-García A., et al. (2016). Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer. Oncotarget 7, 47565–47575. 10.18632/oncotarget.10206 - DOI - PMC - PubMed
    1. Andradas C., Caffarel M. M., Pérez-Gómez E., Salazar M., Lorente M., Velasco G., et al. (2011). The orphan G protein–coupled receptor GPR55 promotes cancer cell proliferation via ERK. Oncogene 30, 245–252. 10.1038/onc.2010.402 - DOI - PubMed
    1. Barbado M. V., Medrano M., Caballero-Velázquez T., Álvarez-Laderas I., Sánchez-Abarca L. I., García-Guerrero E., et al. (2017). Cannabinoid derivatives exert a potent anti-myeloma activity both in vitro and in vivo. Int. J. Cancer 140, 674–685. 10.1002/ijc.30483 - DOI - PubMed
    1. Blasco-Benito S., Seijo-Vila M., Caro-Villalobos M., Tundidor I., Andradas C., García-Taboada E., et al. (2018). Appraising the “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem. Pharmacol. 157, 285–293. 10.1016/j.bcp.2018.06.025 - DOI - PubMed
    1. Caffarel M. M., Andradas C., Pérez-Gómez E., Guzmán M., Sánchez C. (2012). Cannabinoids: a new hope for breast cancer therapy? Cancer Treat. Rev. 38, 911–918. 10.1016/j.ctrv.2012.06.005 - DOI - PubMed

LinkOut - more resources