The Impact of Cannabinoids on Breast Cancer Cell Lines: A Meta-Analysis and Systematic Review of Antitumoral Effects

^*Corresponding Author: David Tovar Parra, Department of Oncology, Biobayter, Bogotá, Colombia

Citation: Salazar LL, Gill-Quinones S, Bonnici L, Parra DT. (2024) The Impact of Cannabinoids on Breast Cancer Cell Lines: A Meta-Analysis and Systematic Reviewof Antitumoral Effects. J Can Ther Res. 4(1):1-18.

Table 1: Summary of the studies included in the systematic review and meta-analysis.

These studies were conducted in different countries around the world and were published between 2010 and December 2022. To ensure the reliability of the analysis, a rigorous bias assessment was performed using the CCSQEG method. As a result, six articles were excluded from the analysis due to identified biases (Supplementary material S2). Additionally, three articles did not provide complete data on CBD for all the analyses conducted, and thus they were not included in the final evaluation.

A total of 10 articles were thoroughly analyzed for all the required assessments. The experimental procedure aimed to evaluate the effects of various cannabinoid-derived compounds on breast cancer cell lines, including both those with positive hormone receptors and triple-negative cell lines. Cell densities ranging from 2.5x 10^3 to 10 x 10^3 were utilized, and different concentrations of the compounds were introduced to the culture media. The standard compounds were tested within the concentration range of 0-200 µM, while extracts were tested within the range of 0-500 µM. After an incubation period of 24 to 72 hours, the cell viability was measured.

To determine viability, cellular metabolic activity methods such as MTT, XTT, MTS, and Reassuring were employed. Furthermore, the impact of different cannabinoid compounds on apoptosis was assessed using Annexin/PI and apoptosis detection tests. Cell migration and invasion were analysed using the Boyden chamber technique, and the cell cycle was studied through the propidium iodide (PI) method. However, the collected data from these assessments were deemed insufficient to be included in this systematic analysis.

Cell lines used in the studies

In the context of the analyzed 10 articles, a total of 10 distinct cell lines were investigated, encompassing both triple-negative and positive receptor cell lines. Among the triple-negative breast cancer cell lines, three were investigated: SUM 159, an invasive and metastatic line; MDA-MD-231, a highly invasive line; and 6D, a clone selected from non-invasive MCF-7 cells [21-22]. Additionally, the cell line SK-BR-3, characterized by HER2 expression, and several cell lines with positive hormone receptors and non-metastatic properties including MCF7, T47D, and ZR-75-1 were also examined [21-23]. Notably, one article also involved the use of a non-tumoral breast cell line, MCF10A, for comparison with tumoral breast cancer cell lines [25].

The analyzed cannabinoids

Cannabinoids, are categorized into three maingroups: endocannabinoids, synthetic cannabinoids, and phytocannabinoids derived from plants, were the focus of analysis in this study [25]. The data examined in the article revealed a diverse range of plant cannabinoid extracts and pure compounds, showcasing heterogeneity among them. Notably, the studied cannabinoids included Δ⁹-THC, CBG, CBN, and CBD. Among these compounds, CBD emerged as the most extensively studied in terms of its effects on breast cancer cell lines, with sufficient data available to describe its impact.

Determination of the effect of cannabinoids on breast cancer cell viability

To determine the activity of different cannabinoids on breast cancer cell lines, data extraction was performed from all relevant articles. Several parameters were considered which include the number of cells used, the concentration of compounds, and the 50% inhibitory concentration (IC50) for each cell line and compound. The extensively studied compounds included THC, CBD, and total extracts.  To analyse the association between the effects of cannabinoids and cell viability, averages were calculated for each compound and subgroup of cell lines which include total cell lines, cell lines with positive receptors, and triple-negative cell lines. The obtained data was used to determine the effect of cannabinoids on breast cancer cells and their impact on cell viability. The average IC50 for all analyzed cells was 9.0 µM for CBD and 12.2 µM for THC. For cell lines with positive receptors, the average IC50 was 10.8 µM for CBD and 14.5 µM for THC, while for triple-negative cells, the average IC50 was 7.5 µM for CBD and 9.5 µM for THC.

From the comparison of results between pure compounds and extracts, it was identified that higher concentrations of extracts were required to achieve similar outcomes compared to CBD and THC compounds. In all three analyzed groups, THC exhibited greater variability in inhibiting cell viability and proliferation of tumor cells than CBD. In addition, the data did not allow for a determination of the effect of THC on cell viability. As a preliminary finding, CBD inhibited the proliferation of breast cancer tumor cells, regardless of their classification.

The results of the meta-analysis revealed significant findings regarding the protective effect of CBD against tumour growth in breast cancer cell lines. The odds ratio (OR) was calculated to be 0.531 with a 95% confidence interval (CI) from 0.429 to 0.656, and a p-value less than 0.001 (Figure 3). These results indicate a strong association between CBD administration and the inhibition of tumour growth in breast cancer cells.

Figure 3: The forest plot shows the CBD influence on the viability of triple-negative and receptor-positive breast cancer cells.

Furthermore, the positive effect of CBD was observed across different types of breast cancer cell lines. In cell lines with positive receptors, the odds ratio was 0.579 with a CI 95% of 0.476 to 0.704, and a p-value less than 0.001 (Figure 4). This suggests that CBD effectively suppresses tumor growth in breast cancer cells expressing positive receptors.

Figure 4: The forest plot of the results of the CBD effect on the viability of breast cancer cells with positive receptors.

Similarly, in triple-negative cell lines, the odds ratio was 0.670, with a 95% CI of 0.594 to 0.755, and a p-value less than 0.001 (Figure 5). This signifies that CBD exhibits its protective effect against tumor growth even in the absence of hormone receptors, which is a characteristic feature of triple-negative breast cancer. The data from this meta-analysis provide strong evidence supporting the use of CBD for inhibiting tumor growth and promoting cell viability in breast cancer cell lines, irrespective of receptor status.

Figure 5: Results of the CBD effect on the viability of triple-negative breast cancer cells.

The standard error-based funnel plot show Figure 6 shows no significant asymmetry making it unlikely that the observed association was caused by publication bias.

Figure 6: Standard error-based funnel plot of the result of relationship between CBD and all breast cancer cell lines.

Effect of cannabinoids on cellular division

In the context of investigating the effects of various cannabinoid derivatives on breast cancer cell lines, a comprehensive set of experiments were conducted to elucidate their impact on cell cycle progression. To achieve this, a combination of propidium iodide (PI) staining and flow cytometry analysis was employed, enabling the determination of the distribution of cells across different cell cycle phases, namely G0/G1, S, and G2/M.

The results obtained from these experiments revealed an intriguing finding regarding the potential of CBD to induce cell cycle arrest in breast cancer cells. Specifically, CBD demonstrated the remarkable ability to specifically arrest the cell cycle at the G1 phase when administered at concentrations below 2.5 µM in MDA-MD-231 cells, in comparison to the control group [26]. Furthermore, similar outcomes were observed in the MCF7 cell line, another well-established breast cancer model. In this case, both CBD and another prominent cannabinoid, THC, exhibited a significant arrest in the G0/G1 phase when administered at concentrations of 5 µM, as compared to the negative control [27]. These experimental findings provide valuable insights into the specific effects of CBD and THC on the cell cycle distribution of breast cancer cells.

Effect of cannabinoids on the induction of apoptosis

Various techniques were employed to investigate the effects of cannabinoids on apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential loss, and caspase 9 or 7 activity in MCF7 cells. The methods used included the Cell Death Detection ELISA PLUS kit, Annexin V-CF Blue, 7-Aminoactinomycin D (7-AAD), Western Blot, and others. Both CBD and THC were found to enhance ROS production. Additionally, the activation of caspases 7 and 9 was observed within two days at concentrations below 10 µM [27]. Notably, CBD treatment resulted in greater cell death in the MDA-MD-231 cell line compared to the MCF7 and MCF10A cell lines. This phenomenon was attributed to the higher levels of ROS induced by CBD, distinguishing it from other compounds like THC, CBG, and CBN [24].

Cannabinoids` effect on breast cancer cell line ability to migrate and invade

Migration and invasion processes play a crucial role in modulating the epithelial-mesenchymal transition and cancer progression. The effects of different cannabinoid compounds were investigated for their effect on the migratory and invasive capacity of breast cancer cell lines using the Boyden chamber and the wound healing assay. In a wound healing assay, treatment with CBD at 6 µM diminished the migratory capacity of MDA-MD-231 and SUM159 cells and reduced the expression of MMP2 and MMP9 [31]. Furthermore, treatment of  MDA-MB-231 cells with CBD significantly reduced the expression of proteins such as Integrin α-5, Twist, Glypican-1, Glypican-6, and Smad-2 compared to the negative control [26]. CBD at concentrations below 10 µM induced a reduction in the number of Ki-67 positive  metastatic MDA-MB23 cells (a marker of cellular proliferation) [28] and inhibited the wound closure of the 6D cell line (MCF-7 with malignant phenotype) [22].

Discussion

Breast cancer is a major health concern that affects millions of women globally. Tumour cells stop responding to existing treatments and become chemoresistant. Therefore, the development of novel treatment strategies is essential to provide treatment alternatives and improve the survival rate [3, 30]. Cannabinoids are one of the options that have been investigated for their effects on different breast tumours [27, 30]. The limited studies available on the effect of cannabinoid treatment on breast cancer show that concentrations above 15 µM of CBD and THC can reduce the viability of positive receptor cells lines (MCF-7, T47D, and ZR-75-1) between 30 - 40%  and up to 50% for triple-negative cell lines (SUM159 and  MDA-MD-231) [22, 24, 31-33].

Studies have demonstrated that both THC and CBD have anticancer activities in different tumor cell lines. For instance, treatment of head and neck squamous cell carcinoma (HNSCC) and the human brain cancer cell line U87MG with low concentrations of CBD and CBD and THC combination caused a significant reduction in cell viability in a time-dependent manner [34-35]. Lung cancer cell lines, A549 and H1299 treated with CBD for 72 hours showed a cytotoxic effect [36]. In leukemias, CBD and THC treatments cause cell cycle arrest, by increasing the percentage of cells in the G0/G1 phase via several mechanisms. For instance, in chronic myeloid leukemia, it has been reported that CBD inhibited the transient receptor potential vanload type-2 (TRPV2), and in multiple myeloma, THC induced cell cycle arrest in the G1 phase after 24 hours post-treatment [37-39]. Similarly, in cholangiocarcinoma and gastric cancer, CBD induced cell cycle arrest at G0/G1and decreased the number of cells in the S phase by inducing DNA damage, interacting with TRPV channels and inhibiting Cyclin-dependent kinase 2 or cyclin E [40-42]. In the triple negative breast cancer cell line MDA-MD-231, CBD induced cell cycle arrest as shown by an increase of cells in the G1 and sub-G0 phases and a decrease in the number of cells in the S phase [26, 31, 43, and 44].

According to the available data, treatment with CBD in a dose-dependent manner induce apopt osis and autophagy by up regulating the expression of Caspase-3, -7, and -9 in HNSCC (SCC15, Hep2, and FaDu) [34, 45, 46]. Treatment of acute lymphoblastic leukemia cells with CBD caused an increase in ROS, LC3-II, and calcium metabolism [45].  Similarly, in estrogen receptor-positive and negative breast cancer cells treated with CBD  and the combination of CBD with other cannabinoids or chemotherapeutic drugs also induce autophagy and apoptosis in a concentration-dependent manner by inducing endoplasmic reticulum stress signified by the increase in LC3-I, LC3-II, pro-PARP, cleaved PARP and cleavage of procaspases -3, -7, and -9 [31, 47, 48].

Metastatic disease has a high mortality rate [49]. Cannabinoids have shown anti-invasion and anti-migration effects. Several research groups mainly conducted in vitro assays with glioblastoma, adenocarcinoma, HNSCC, and mesothelioma cells to test the effect of CBD at various concentrations [34, 49-51]. From the limited available studies, treatment of MDA-MB-23 with CBD caused a reduction in cell migration by inhibiting cAMP-dependent protein kinase A, ERK, and AKT signalling, and modulating the tumour microenvironment [28, 32, 52]. In addition, it was shown through a colony formation assay that treatment with CBD for 24 hours reduced the ability of chronic myeloid leukemia cell lines to form colonies, reduce the size of the colonies of cholangiocarcinoma cell lines (HuCC-T1 and  Mz-ChA-1 ) and induce a cytotoxic effect in HNSCC [34, 37, 40]. Collectively, recent studies show that CBD has anti-migratory effects across different types of cancer cell lines including breast cancer, hence making CBD a potential therapeutic option. One of the major limitations in our meta-analysis is that few studies investigated the anti-cancer effect of cannabinoids on breast cancer cell lines. Furthermore, these studies used similar approaches to explore the anti-cancer effect of cannabinoids. Not all breast cancer cell lines were evaluated, and most of the studies tested the effect of CBD, with only a few studies testing the effect of THC, CBN, and CBG.

Conclusion

Our systematic review and meta-analysis identified that CBD and THC show anti-cancer effects on several cancer cell lines by inhibiting cellular proliferation, migration and invasion and promoted cell death by inducing apoptosis and autophagy. Collectively, studies show that CBD and THC may have potential to be used as a treatment individually or in combination with other chemotherapeutic agents. Although the most tested cannabinoids on breast cancer cell lines are CBD and THC, it is worthwhile to investigate the anti-cancer effect of other cannabinoids such as cannabigerovarin, cannabigerolic acid and cannabichromevarin. Finally, more studies are required to identify the mechanisms by which cannabinoids exert their anti-cancer effects.

Declaration

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Availability of data and materials: Not applicable

Competing interests: Not applicable

Funding: This article has been funded through Biobayter.

Authors' contributions

D.T, data collection or analysis and interpretation of data; statistical analysis; writing of the manuscript or critical review of important intellectual content; critical review of the literature, administrative, technical, and material support. L.L.S, the study concept and design; analysis and interpretation of data; statistical analysis; writing of the manuscript or critical review of important intellectual content; data collection, analysis, and interpretation; critical review of the literature, final approval of the final version of the manuscript. S.G.Q, data collection or analysis and interpretation of data; statistical analysis; writing of the manuscript or critical review of important intellectual content; critical review of the literature, administrative, technical, and material support. L.B. interpretation of data; statistical analysis; writing of the manuscript; critical review of important intellectual content; critical review of the literature.

Acknowledgements

Not applicable

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