Synergistic Interactions of Cannabidiol with Chemotherapeutic Drugs in MCF7 Cells: Mode of Interaction and Proteomics Analysis of Mechanisms

Abstract

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN−38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after the treatments were assessed via flow cytometry. The molecular mechanisms of CBD and the most promising combinations were investigated via label-free quantification proteomics. A strong synergy was observed across all synergy models at different molar ratios of CBD in combination with SN−38 and VIN. Intriguingly, synergy was observed for CBD with all chemotherapeutic drugs at a molar ratio of 636:1 in almost all synergy models. However, discording synergy trends warranted the validation of the selected combinations against different models. Enhanced apoptosis was observed for all synergistic CBD combinations compared to monotherapies or negative controls. A shotgun proteomics study highlighted 121 dysregulated proteins in CBD-treated MCF7 cells compared to the negative controls. We reported the inhibition of topoisomerase II β and α, cullin 1, V-type proton ATPase, and CDK-6 in CBD-treated MCF7 cells for the first time as additional cytotoxic mechanisms of CBD, alongside sabotaged energy production and reduced mitochondrial translation. We observed 91 significantly dysregulated proteins in MCF7 cells treated with the synergistic combination of CBD with SN−38 (CSN−38), compared to the monotherapies. Regulation of telomerase, cell cycle, topoisomerase I, EGFR1, protein metabolism, TP53 regulation of DNA repair, death receptor signalling, and RHO GTPase signalling pathways contributed to the proteome-wide synergistic molecular mechanisms of CSN−38. In conclusion, we identified significant synergistic interactions between CBD and the five important chemotherapeutic drugs and the key molecular pathways of the combination of CBD and CSN−38 in MCF7 cells. Further in vivo and clinical studies are warranted to evaluate the implementation of CBD-based synergistic adjuvant therapies for breast cancer.

Mechanisms of Cannabidiol (CBD) in Cancer Treatment: A Review

“…Chemotherapy is one of the most frequently applied cancer treatments. In recent years, the potential synergistic effects of CBD and chemotherapeutic drugs against breast cancer have also been evaluated [ 38 , 39 , 40 ]. Doxorubicin (DOX) is a chemotherapy drug that is commonly used to treat many types of cancer, such as breast cancer, bladder cancer, and lymphoma.…”

“…Importantly, CBD EVs sensitized MDA-MB-231 xenograft tumors to DOX through the suppression of pro-inflammatory proteins and the activation of pro-apoptotic markers [ 39 ]. In addition to DOX, Alsherbiny et al evaluated the effects of a combination of CBD with four more chemotherapeutic drugs, including docetaxel, paclitaxel, vinorelbine, and 7-ethyl-10-hydroxycamptothecin in MCF7 cells [ 40 ]. Enhanced effects were observed with the combination of CBD (38.42–64.6 µM) and all the chemotherapeutic drugs, while the strongest synergism was found between CBD, vinorelbine, and 7-ethyl-10-hydroxycamptothecin.…”

A Comprehensive Review on the Techniques for Extraction of Bioactive Compounds from Medicinal Cannabis

“…CBG can interact with 5-hyroxytryptamine (5-HT1A) and α-2 adrenoreceptors to have therapeutic potential in Parkinson’s, Huntington’s, inflammatory bowel diseases, and multiple sclerosis [ 41 ]. The lucrative non-psychoactive CBD displayed potential therapeutic effects in neuropsychiatric disorders, cancers, and pain management with diverse molecular targets and signalling pathways [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Cannabielsoin (CBE) was recently reported to control neuropathic pain via the modulation of the Wnt/β-catenin pathway [ 49 ].…”

The Combination Effect of Ceftriaxone and Chloramphenicol on Staphylococcus aureus Isolate of Diabetic Gangrene

“…However, inhibition zone diameter of the combination was higher than CML 7.5 μg/mL and it has a moderate activity. CML showed a low antibacterial effect due to the dose used and the less sensitivity of them to S. aureus (Yutaka, 2020;Alsherbiny et al, 2021).…”

“…The combination was selected to expand the spectrum of bacteria also (Kothari et al, 2022). Actually, the aims of antibacterial combination to increase potency, extend spectrum, reduce resistance and toxicity (Alsherbiny et al, 2021;Kothari et al, 2022). However, incorrect selection of antibacterial combination and the dose produce therapy failure (Gilbert et al, 2010;Parkunan et al, 2019).…”