Cannabidiol as a novel therapeutic agent in breast cancer: evidence from literature

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“Background: Breast cancer is one of the most prevalent cancers worldwide, posing significant challenges due to its heterogeneity and the emergence of drug resistance. Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, has recently gained attention for its potential therapeutic effects in breast cancer.

Objective: This review aims to evaluate the antitumor effects of CBD in breast cancer treatment by synthesizing preclinical and clinical evidence, elucidating its mechanisms of action, and exploring its translational potential.

Methods: A systematic review was conducted following PRISMA guidelines. A comprehensive search was performed across PubMed, Google Scholar, Web of Science, and Scopus databases, using keywords such as “Cannabidiol,” “CBD,” “Breast Cancer,” “Therapeutic Agent,” and “Antitumor Effects.” A total of 1,191 articles were initially identified. After duplicate removal and eligibility screening, 34 studies published between 1998 and 2025 were selected, including in vitro, in vivo, and clinical investigations. Studies were assessed based on PRISMA recommendations, considering inclusion criteria such as CBD’s impact on apoptosis, cell proliferation, tumor progression, and molecular mechanisms.

Results: CBD demonstrated significant anticancer effects, including induction of apoptosis, inhibition of cell proliferation, suppression of metastasis, and modulation of the tumor microenvironment. Mechanistically, CBD modulates key pathways such as PI3K/Akt, mTOR, and PPARγ and interacts with CB1, CB2, and non-cannabinoid receptors. Preclinical studies showed CBD’s efficacy, particularly in triple-negative breast cancer (TNBC), while limited clinical trials highlighted its potential as an adjunct to conventional therapies.

Conclusion: CBD offers a promising therapeutic approach for breast cancer, especially for aggressive subtypes like TNBC. However, challenges such as variability in study design, lack of standardized protocols, and limited clinical validation hinder its clinical application. Future research should focus on conducting robust clinical trials, identifying predictive biomarkers, and optimizing combinatorial therapies to integrate CBD into personalized cancer treatment strategies.”

https://pubmed.ncbi.nlm.nih.gov/40275168/

“CBD holds significant promise as a complementary or standalone therapeutic agent in breast cancer treatment, particularly in TNBC, where conventional options are limited. However, clinical validation through well-designed trials, biomarker identification, and safety profiling remains imperative before widespread clinical adoption. Future studies should focus on optimizing combinatorial therapies, investigating long-term effects, and refining pharmacological formulations to bridge the gap between preclinical findings and clinical application. By addressing these challenges, CBD could potentially redefine breast cancer management strategies, offering a safer, more effective, and targeted approach to treatment.”

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-025-14175-z

Cannabidiol for Scan-Related Anxiety in Women With Advanced Breast Cancer: A Randomized Clinical Trial

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“Importance: Early evidence from studies outside of oncology has suggested that cannabidiol (CBD) may have anxiolytic effects without neuropsychiatric risks. An understanding of oral CBD in patients with cancer-related anxiety is urgently needed.

Objective: To determine whether a single 400-mg oral dose of a US Food and Drug Administration-approved CBD improves clinical anxiety in an oncologic population.

Design, setting, and participants: This phase II, double-masked, placebo-controlled, randomized clinical trial was performed at the Dana-Farber Cancer Institute’s Breast Oncology Center from November 2, 2021, through March 1, 2023. Women aged 18 years or older with advanced breast cancer and baseline clinical anxiety were included.

Interventions: Patients were randomized 1:1 to receive oral CBD, 400 mg, vs placebo within 48 hours before a scan assessing tumor burden.

Main outcomes and measures: The primary end point was a between-arm comparison of change scores on the afraid subscale of the Visual Analog Mood Scale (VAMS) before and 2 to 4 hours after study drug ingestion. The VAMS scores were converted to T-scores to facilitate interpretation of mood change (>20 indicates a reliable change, >30 indicates both a reliable and clinically significant change). Exploratory outcomes included between-arm comparisons of anxiety levels 2 to 4 hours after study drug ingestion, between-arm comparisons of change scores on other VAMS subscales, and safety.

Results: Among the 50 participants, 25 were randomized to the placebo arm (mean [range] age, 57 [37-81] years) and 25 were randomized to the CBD arm (mean [range] age, 60 [30-79] years). The primary end point of VAMS afraid subscale change score, although numerically greater in the CBD arm, was not significantly different between arms (mean [SD]: CBD, -19.1 [15.4]; placebo, -15.0 [10.9]; P = .37). The secondary outcome directly comparing anxiety levels between arms 2 to 4 hours after study drug ingestion demonstrated significantly lower VAMS afraid T-scores for participants who received CBD compared with those receiving placebo (mean [SD]: CBD, 51.5 [12.8]; placebo, 58.0 [11.6]; P = .02). No grade 3 or 4 toxic effects were reported.

Conclusions and relevance: The findings of this randomized clinical trial show that CBD can be used safely in women with advanced breast cancer and clinical anxiety. Although the study did not meet its primary end point comparing preingestion vs postingestion anxiety change scores between study arms, anxiety levels in the CBD arm were significantly lower 2 to 4 hours after ingestion, suggesting a possible anxiolytic effect and warranting further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39680411/

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2828077

Cannabidiol effects in stem cells: A systematic review

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“Stem cells play a critical role in human tissue regeneration and repair. In addition, cancer stem cells (CSCs), subpopulations of cancer cells sharing similar characteristics as normal stem cells, are responsible for tumor metastasis and resistance to chemo- and radiotherapy and to tumor relapse.

Interestingly, all stem cells have cannabinoid receptors, such as cannabidiol (CBD), that perform biological functions. The aim of this systematic review was to analyze the effect of CBD on both somatic stem cells (SSCs) and CSCs.

Of the 276 articles analyzed, 38 were selected according to the inclusion and exclusion criteria. A total of 27 studied the effect of CBD on SSCs, finding that 44% focused on CBD differentiation effect and 56% on its protective activity. On the other hand, 11 articles looked at the effect of CBD on CSCs, including glioblastoma (64%), lung cancer (27%), and breast cancer (only one article).

Our results showed that CBD exerted a differentiating and protective effect on SCCs. In addition, this molecule demonstrated an antiproliferative effect on some CSCs, although most of the analyses were performed in vitro.

Therefore, although in vivo studies should be necessary to justify its clinical use, CBD and its receptors could be a specific target to act on both SSCs and CSCs.”

https://pubmed.ncbi.nlm.nih.gov/39653426/

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.2148

Discovery of Ring-Annulated Analogues of Cannabidiol as Potential Anticancer Agents: Synthesis and Biological Evaluation

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“Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived from Cannabis sativa and its potential therapeutic effects extend beyond its well-known antiepileptic properties. Exploring CBD and its analogues as anticancer agents has gained significant attention in recent years.

In this study, a series of novel ring-annulated analogues of CBD with oxazinyl moiety were synthesized and evaluated for their antiproliferative effect.

The analogues 4d and 4h demonstrate promising activity against breast and colorectal cancer. Furthermore, mechanistic insights revealed that the identified candidates arrest the G1 phase of the cell cycle and induce apoptosis via the mitochondrial pathway in breast cancer cell lines.

Notably, CBD ring-annulated analogues 4d or 4h exhibit enhanced solubility, better metabolic stability, and lowered cytochrome P450 (CYP) inhibition liability compared to CBD.

These multifaceted attributes highlight the potential of cannabinoid-based candidates for further preclinical development.”

https://pubmed.ncbi.nlm.nih.gov/39563806/

https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00233

Combinatorial effects of cannabinoid receptor 1 and 2 agonists on characteristics and proteomic alteration in MDA-MB-231 breast cancer cells

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“Breast cancer is the most common cancer diagnosed in women worldwide. However, the effective treatment for breast cancer progression is still being sought.

The activation of cannabinoid receptor (CB) has been shown to negatively affect breast cancer cell survival.

Our previous study also reported that breast cancer cells responded to various combinations of CB1 and CB2 agonists differently. Nonetheless, the mechanism underlying this effect and whether this phenomenon can be seen in other cancer characteristics remain unknown. Therefore, this study aims to further elucidate the effects of highly selective CB agonists and their combination on triple-negative breast cancer proliferation, cell cycle progression, invasion, lamellipodia formation as well as proteomic profile of MDA-MB-231 breast cancer cells.

The presence of CB agonists, specifically a 2:1 (ACEA: GW405833) combination, prominently inhibited colony formation and induced the S-phase cell cycle arrest in MDA-MB-231 cells. Furthermore, cell invasion ability and lamellipodia formation of MDA-MB-231 were also attenuated by the exposure of CB agonists and their 2:1 combination ratio. Our proteomic analysis revealed proteomic profile alteration in MDA-MB-231 upon CB exposure that potentially led to breast cancer suppression, such as ZPR1/SHC1/MAPK-mediated cell proliferation and AXL/VAV2/RAC1-mediated cell motility pathways.

Our findings showed that selective CB agonists and their combination suppressed breast cancer characteristics in MDA-MB-231 cells. The exposure of CB agonists also altered the proteomic profile of MDA-MB-231, which could lead to cell proliferation and motility suppression.”

https://pubmed.ncbi.nlm.nih.gov/39527598/

“Our study demonstrated that the presence of CB agonists hindered breast cancer cell growth, cell cycle progression, invasion through extracellular matrices and lamellipodia formation. The exposure of specific combination of CB1 and CB2 agonists also enhanced their breast cancer suppression effects. Moreover, breast cancer survival and motility-related proteins affected by the presence of these agonists suggesting the potential pathways underlying their effects were also depicted in this study.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0312851

Improved Therapeutic Efficacy of Doxorubicin Chemotherapy With Cannabidiol in 4T1 Mice Breast Cancer Model

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“Background: High dose chemotherapy is one of the therapeutic strategies for breast cancer and doxorubicin (DOX) as a chemotherapy agent is widely used. DOX indication is limited due to its dose-depended cardiotoxicity. Recently, cannabidiol (CBD) shows antitumoral and cardioprotective effects, so we hypothesized that CBD administration with high-dose DOX chemotherapy can improve anticancer activity and reduce cardiotoxic side effects.

Method: Mice breast cancer model established by injecting 4T1 cell lines. One group was not injected by 4T1 cells as a not cancerous group and received normal saline (NS, 0.1 mL). In cancerous groups, first group was considered as cancerous control and received NS (0.1 mL); the second group received CBD (5 mg/kg, IP) on Days 1,7, and 14; in the third group DOX (5 mg/kg, IV) as CBD schedule was administrated; the fourth group treated with CBD 1 day before DOX injection as pretreatment, and the last group was treated with CBD and DOX at same time with previous doses and schedules. On Day 21, all mice were sacrificed, heart and lungs tissues were obtained and histological sections were isolated. SOD2, iNOS, MMP2, MMP9 were evaluated through western blot and TUNEL test preformed for breast tumor.

Results: Tumor size and weight significantly decreased in DOX, pretreatment CBD + DOX and CBD + DOX groups. Administration of CBD with DOX could not prevent weight loss. TUNEL test demonstrated the highest tumor cell apoptosis in pretreatment CBD + DOX and CBD + DOX. In lungs belonged to CBD + DOX, there was not any sign of metastasis. Cardiac histopathological examination of pretreatment CBD + DOX and CBD + DOX did not show any sign of congestion or inflammation. In CBD + DOX SOD2 increased, also iNOS, MMP2, and MMP9 decreased compared to DOX.

Conclusions: This study demonstrated that simultaneous administration of CBD and DOX can increase antitumoral effect and reduce DOX cardiotoxicity. Nevertheless, CBD can induce cardiotoxicity as administrated alone.”

https://pubmed.ncbi.nlm.nih.gov/39503169/

“This study demonstrated the potent efficacy of cannabidiol in mouse breast cancer model with high-dose chemotherapy on the antitumor, anti-metastasis and cardioprotective roles against doxorubicin. Simultaneous administration of cannabidiol with high-dose doxorubicin not only improved the antitumor and anti-metastasis efficacy, but also could reduce cardiotoxicity by decreasing MMP2 and MMP9 and improving cardiac function by decreasing iNOS. Furthermore, cannabidiol could improve antioxidant system by increasing SOD2. Eventually, these findings demonstrated cannabidiol as a potential effective agent in coadministration with doxorubicin at the same time in improving anticancer effects and reducing cardiotoxicity.”

https://onlinelibrary.wiley.com/doi/10.1002/cam4.70395

The molecular anti-metastatic potential of CBD and THC from Lebanese Cannabis via apoptosis induction and alterations in autophagy

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“The medicinal plant Cannabis sativa L. (C. sativa) is currently being extensively studied to determine the full extent of its therapeutic pharmacological potential. Δ9-tetrahydocannabinol (THC) and cannabidiol (CBD) are the most thoroughly investigated compounds.

We aimed to explore the anticancer activity of cannabinoids mixture isolated from the Lebanese C. sativa plant in ratios comparable to the local medicinal plant, to elucidate its mechanism of action in breast cancer cells in vitro.

Cells were subjected to cytotoxicity assay, cell cycle analysis, Annexin V/PI dual staining, cell death ELISA, immunofluorescence, in addition to western blot analysis of apoptotic and autophagy markers. We further evaluated the anti-metastatic effect of cannabinoids on MDA-MB-231 using the scratch wound-healing, trans-well migration and invasion assays.

Our results revealed the promising therapeutic benefits of CBD/THC on inhibiting the growth of breast cancer cells by promoting cellular fragmentation, phosphatidylserine translocation to the outer membrane leaflet and DNA fragmentation in both cell lines while inhibiting the motility of the triple negative breast cancer cells.

In our study, CBD/THC mixture was found to exhibit a pro-apoptotic activity via the activation of the mitochondrial apoptotic pathway, independent from ROS production while also suggesting the activation of a caspase-dependent apoptotic pathway. Even though autophagy was altered upon exposure to the cannabinoid mixture, our data suggested that it is not the mechanism responsible of inducing cell death.

In conclusion, our study demonstrates the promising therapeutic benefits of CBD and THC isolated from the Lebanese C. sativa plant on breast cancer cells in vitro.”

https://pubmed.ncbi.nlm.nih.gov/39463375/

“Our study showed that CBD and THC isolated from the Lebanese cannabis strains, in ratios comparable to the medicinal plants, exhibit promising effect on breast cancer cell lines. The anticancer activity of this mixture was revealed by its ability to promote cellular fragmentation, phosphatidylserine translocation and DNA fragmentation while inhibiting the motility of aggressive breast cancer cells. Our results showed a pro-apoptotic activity on MDA-MB-231 and MCF-7 cells via the activation of the intrinsic apoptotic pathway. Moreover, we found that even if autophagy was altered in breast cancer cell lines, it is not the major mechanism leading to cellular death. Also, we demonstrated that this mixture was effective in halting the progression of breast cancer cells via the suppression of cancer cell migration and invasion.”

https://www.nature.com/articles/s41598-024-76340-x

Molecular Targets of Minor Cannabinoids in Breast Cancer: In Silico and In Vitro Studies

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“Background: Breast cancer therapy has been facing remarkable changes. Classic treatments are now combined with other therapies to improve efficacy and surpass resistance. Indeed, the emergence of resistance demands the development of novel therapeutic approaches. Due to key estrogen signaling, estrogen receptor-positive (ER+) breast cancer treatment has always been focused on aromatase inhibition and ER modulation. Lately, the effects of phytocannabinoids, mainly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have been evaluated in different cancers, including breast. However, Cannabis sativa contains more than 120 phytocannabinoids less researched and understood.

Methods: Here, we evaluated, both in silico and in vitro, the ability of 129 phytocannabinoids to modulate important molecular targets in ER+ breast cancer: aromatase, ER, and androgen receptor (AR).

Results: In silico results suggested that some cannabinoids may inhibit aromatase and act as ERα antagonists. Nine selected cannabinoids showed, in vitro, potential to act either as ER antagonists with inverse agonist properties, or as ER agonists. Moreover, these cannabinoids were considered as weak aromatase inhibitors and AR antagonists with inverse agonist action.

Conclusions: Overall, we present, for the first time, a comprehensive analysis of the actions of the phytocannabinoids in targets of ER+ breast tumors, pointing out their therapeutic potential in cancer and in other diseases.”

https://pubmed.ncbi.nlm.nih.gov/39338407/

“From the best of our knowledge, this is the first study exploring the molecular targets of minor cannabinoids and, together with previous studies, it reinforces the importance and therapeutic potential of cannabinoids in breast cancer, paving the way for novel and alternative therapeutic approaches and highlighting the medicinal potential of Cannabis.”

https://www.mdpi.com/1424-8247/17/9/1245

Cannabidiol enhances Atezolizumab efficacy by upregulating PD-L1 expression via the cGAS-STING pathway in triple-negative breast cancer cells

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“The treatment of patients with triple negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients with low reactivity to atezolizumab. As there is a lack of alternative treatment options, new anti-cancer drugs are urgently needed to enhance atezolizumab reactivity against TNBC. Recent strategies have focused on regulating the expression of programmed death-ligand 1 (PD-L1) or enhancing immune response activation by combining anti-cancer drugs with immune checkpoint inhibitors (ICIs).

Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anti-cancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells.

Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anti-cancer immune responses remains to be explored.

In this study, we found that CBD stimulated PD-L1 expression in TNBC cells, which significantly induced the CBD-mediated cGAS-STING pathway activation. Taken together, we demonstrated that the combination of CBD and anti-PD-L1 antibody enhances the anti-cancer immune response in vitro and in vivo experiments.

Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with ICIs in TNBC patients.”

https://pubmed.ncbi.nlm.nih.gov/39226389/

https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-23-0902/747763/Cannabidiol-enhances-Atezolizumab-efficacy-by

Cannabinoids and triple-negative breast cancer treatment

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“Triple-negative breast cancer (TNBC) accounts for about 10-20% of all breast cancer cases and is associated with an unfavorable prognosis. Until recently, treatment options for TNBC were limited to chemotherapy. A new successful systemic treatment is immunotherapy with immune checkpoint inhibitors, but new tumor-specific biomarkers are needed to improve patient outcomes.

Cannabinoids show antitumor activity in most preclinical studies in TNBC models and do not appear to have adverse effects on chemotherapy.

Clinical data are needed to evaluate efficacy and safety in humans. Importantly, the endocannabinoid system is linked to the immune system and immunosuppression. Therefore, cannabinoid receptors could be a potential biomarker for immune checkpoint inhibitor therapy or a novel mechanism to reverse resistance to immunotherapy. In this article, we provide an overview of the currently available information on how cannabinoids may influence standard therapy in TNBC.”

https://pubmed.ncbi.nlm.nih.gov/39176080/

“Selective CB2R agonists and antagonists are needed to develop potential anti-cancer drugs that target the endocannabinoid system,”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1386548/full