“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

“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

“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

“Objective: Triple-negative breast cancer presents a significant challenge in oncology due to its complex treatment and aggressive nature. This subtype lacks common cancer cell receptors like estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. This study aimed to identify, through bioinformatic analysis, the key genes associated with triple-negative breast cancer. In addition, CBD analogs with potential inhibitory effects on these genes were evaluated through docking and molecular dynamics.

Methods: Gene expression profiles from the GSE178748 dataset were analyzed, focusing on MDA-MB-231 breast cancer cell lines. Differentially expressed genes were determined through protein-protein interaction networks and subsequently validated. Additionally, the inhibitory effects of cannabidiol analogs on these hub genes were assessed using molecular docking and dynamics.

Results: Analysis of the hub highlighted RPL7A, NHP2L1, and PSMD11 as significant players in TNBC regulation. Ligand 44409296 showed the best affinity energy with RPL7A, while 166505341 exhibited the highest affinity with NHP2L1 and PSMD11, surpassing CBD. Analyses of RMSD, RMSF, SASA, and Gyration Radius indicated structural stability and interactions of the proteins with ligands over time. MMGBSA calculations showed favorable binding energies for the ligands with the target proteins.

Conclusion: In conclusion, this study identified key genes, namely RPL7A, NHP2L1, and PSMD11, associated with triple-negative breast cancer and demonstrated promising interactions with cannabidiol analogs, particularly 44409296 and 166505341. These findings suggest potential therapeutic targets and highlight the relevance of further clinical investigations. Additionally, the ligands exhibited favorable ADME properties and low toxicity, underscoring their potential in future drug development for TNBC treatment.”

https://pubmed.ncbi.nlm.nih.gov/38809637/

https://journal.waocp.org/article_91159.html

“Studies have shown that natural products can induce paraptosis in tumour cell lines. Paraptosis is characterized by cytoplasmic vacuolation arising from the endoplasmic reticulum (ER) and mitochondria. The mechanism of paraptosis is unclear; however, dysregulation of Ca²⁺ homeostasis is believed to affect paraptosis induction.

This study investigated the mechanism of cell death induced by a phytocannabinoid ratio in the MCF7 breast cancer cell line.

The crystal violet assay was used to detect changes in viability and morphology changes were investigated using light and transmission electron microscopy. Various inhibitors, fluorescent staining with high-content screening, and Western blot analysis were used to investigate different cell death mechanisms.

The phytocannabinoid ratio induced significant cell death and cytoplasmic vacuolation in MCF7 cells; however, no apoptosis, necrosis, autophagy, or ferroptosis was detected. Vacuolation induced by phytocannabinoid treatment was inhibited by cycloheximide, suggesting paraptosis induction. The mechanism of paraptosis induction was investigated, and it was found that treatment (1) induced ER dilation and mitochondrial swelling, (2) induced significant ER stress and mitochondrial Ca²⁺ overload and dysfunction, which appeared to be mediated by the voltage-dependent anion channel, and (3) significantly impaired all mitochondrial metabolic pathways.

The data demonstrated that paraptosis induced by the cannabinoid ratio was mediated by Ca²⁺ flux from the ER to the mitochondria.

These findings highlight a novel mechanism of cannabinoid-induced cell death and emphasize the anti-cancer potential of cannabinoid ratios, which exhibited enhanced effects compared to individual cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/38721827/

” In the context of cancer, cannabinoids have primarily been used for their palliative effects to treat the side effects of chemotherapy; however, their tumour-suppressive properties have been known since the first observation of their antitumor effects in 1975.”

https://onlinelibrary.wiley.com/doi/10.1111/cpr.13650

“Cannabis sativa is a well-known plant for its psychoactive effects; however, its many derivatives, such as Cannabidiol (CBD), contain several therapeutic applications. Tetrahydrocannabinol (THC) is the main cannabis derivative responsible for psychoactive properties, while CBD is non-psychotropic. For this reason, CBD has been more exploited in the last decade.

CBD has been connected to multiple anticancer properties, and when combined with photodynamic therapy (PDT), it is possible to eradicate tumors more effectively. In this study, CBD was utilized to treat MCF-7 breast cancer cells, followed by in vitro PDT combination therapy. Conventional breast cancer treatment modalities such as chemotherapy, radiotherapy, etc. have been reported for inducing a number of undesirable side effects, recurrence of the disease, and low quality of life.

In this study, cells were exposed to varying concentrations of CBD (i.e., 1.25, 2.5, 5, 10, and 20 μg/mL) and incubated 12 and 24 h after treatment. The optimal doses were then used in combination therapy. Morphology and biochemical assays, including lactate dehydrogenase (LDH) for membrane integrity, adenosine triphosphate (ATP) for viability, and trypan blue exclusion assay for viability, were used to examine cellular responses after treatments. The optimal concentration was then utilized in Hypericin-Gold nanoparticles mediated PDT combination.

The results revealed that, in a dose-dependent manner, conventional morphological characteristics of cell death, such as vacuolization, blebbing, and floating were observed in treated cells. The biochemical responses demonstrated an increase in LDH, a decrease in ATP, and a reduction in viability. This study demonstrated that CBD induces cell death in MCF-7 breast cancer cells cultured in vitro. The immunofluorescence results of combination therapy indicated that cell death occurred via apoptosis.

In conclusion, this study proposes that the CBD and PDT combination therapy is effective in killing MCF-7 breast cancer cells in vitro by induction of apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/38247877/

https://www.mdpi.com/2073-4409/13/2/187