“Objective: Radiotherapy, which is commonly used for the local control of thoracic cancers, also induces chronic inflammatory responses in the microvasculature of surrounding normal tissues such as the lung and heart that contribute to fatal radiation-induced lung diseases (RILDs) such as pneumonitis and fibrosis. In this study, we investigated the potential of cannabidiol (CBD) to attenuate the irradiation damage to the vasculature. 

Methods: We investigated the ability of CBD to protect a murine endothelial cell (EC) line (H5V) and primary lung ECs isolated from C57BL/6 mice from irradiation-induced damage in vitro and lung ECs (luECs) in vivo, by measuring the induction of oxidative stress, DNA damage, apoptosis (in vitro), and induction of inflammatory and pro-angiogenic markers (in vivo). 

Results: We demonstrated that a non-lethal dose of CBD reduces the irradiation-induced oxidative stress and early apoptosis of lung ECs by upregulating the expression of the cytoprotective mediator heme-oxygenase-1 (HO-1). The radiation-induced increased expression of inflammatory (ICAM-2, MCAM) and pro-angiogenic (VE-cadherin, Endoglin) markers was significantly reduced by a continuous daily treatment of C57BL/6 mice with CBD (i.p. 20 mg/kg body weight), 2 weeks before and 2 weeks after a partial irradiation of the lung (less than 20% of the lung volume) with 16 Gy. 

Conclusions: CBD has the potential to improve the clinical outcome of radiotherapy by reducing toxic side effects on the microvasculature of the lung.”

https://pubmed.ncbi.nlm.nih.gov/39518030/

“In this study, we demonstrate that cannabidiol (CBD), the non-psychogenic component of cannabis, mediates anti-inflammatory and anti-oxidative effects that protect the microvasculature of the lung against radiation-induced damage using in vitro and in vivo murine models. CBD therefore has the potential to improve the clinical outcome of radiotherapy by reducing normal tissue toxicity in the lung.”

https://www.mdpi.com/2072-6694/16/21/3589

“Introduction: A multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern.

Methods: Considering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes.

Results: Our analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFN-g) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKT-CIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation.

Conclusions: Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy.”

https://pubmed.ncbi.nlm.nih.gov/38558822/

“In conclusion, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy and its complete success requires careful consideration of the patients’ genetic backgrounds. Cell lines with KRAS mutation (A549 cells) and EML4-ALK rearrangement (NCI-H2228) appear to be highly responsive in this combinatorial setup. Beyond that, CBD affects NKT subpopulations of CIK cells and may modulate the TRPV2 channel and the p-ERK1/2 pathway. However, the biosafety of a combination of CIK cells and CBD requires further validation in animal models.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1268652/full

“Dasatinib-related resistance frequently occurs and may lead to the failure of chemotherapy; thus, dose interruptions are necessary. Cannabidiol (CBD) has potential for integration with orthodox cancer care.

In this study, we explored the combination effect of CBD and dasatinib on A549 cells. CBD in combination with dasatinib could induce significant synergistic apoptosis in vitro (ZIP > 10) and in vivo. The combination of CBD and low-dose dasatinib exhibited antiproliferative and proapoptotic effects through up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2 in A549 cells. The xenograft mouse model suggested that the combination was more efficient and safer.

In short, CBD and low-dose dasatinib exhibited a synergistic effect on anticancer by targeting the SRC/PI3K/AKT signaling pathway, suggesting a potential therapeutic option for the treatment of lung cancer.”

https://pubmed.ncbi.nlm.nih.gov/38503236/

“In conclusion, we demonstrated that CBD can enhance dasatinib-induced apoptosis and cytotoxicity against lung cancer in vitro and in vivo. Apoptosis-related genes and PI3K/AKT-related signaling were significantly dysregulated in A549 lung cancer cells treated with dasatinib in combination with CBD. These findings indicated that combination therapy of CBD plus low-dose dasatinib is a promising clinical therapy, and the mechanism of the synergistic effect of CBD and dasatinib may be the SRC/PI3K/AKT and Bax/Bcl-2/caspase-3 signaling pathways.”

https://www.sciencedirect.com/science/article/pii/S0753332224003299?via%3Dihub

“Introduction: Lung cancer is the number-one cause of death due to neoplasms worldwide. The 5-year overall survival rate is only 22%. In advanced stages, the therapeutic options are limited to chemotherapy, radiotherapy, molecularly targeted therapy and immunotherapy. Phytocannabinoids, the components of Cannabis sativa, their synthetic derivatives and endogenous cannabinoids have demonstrated anticancer activity in various common cancers – breast, prostate, colorectal and lung cancers, among others. The aim of this review was to assess the potential value of cannabinoids in the treatment of lung cancer.

State of knowledge: The majority of preclinical studies demonstrates that cannabinoids inhibit lung cancer cell viability both in vitro and in vivo. The main mechanism of anticancer  activity is the induction of apoptosis, triggered by activation of CB1, CB2 and TRPV1 receptors or independently via other pathways. Cannabinoids influence the components of the tumour microenvironment – cancer associated fibroblasts, macrophages and lymphokine-activated-killer cells. Cannabinoids alter leukocyte infiltration into anti-cancer proportions, inhibit expression of EGFR and PAI-1 and increase the expression of TIMP-1. As a result they induce cytotoxicity, decrease proliferation, migration and invasive potential of lung cancer cells, suppress angiogenesis and metastasis forming. Patients with advanced lung cancer may also benefit from analgesic, antiemetic and appetite improving properties of cannabinoids.

Summary: Cannabinoids can be a supplementary agent in systemic anticancer therapeutic regimen in the future. The exact mechanisms of action, specific doses in anticancer treatment, routes of administration and interactions with other anticancer drugs has yet to be determined. Thus the clinical studies on cannabinoids in lung cancer should be performed in the future.”

https://apcz.umk.pl/JEHS/article/view/39529

“Lung cancer remains the most chronic form of cancer and the leading cause of cancer mortality in the world. Despite significant improvements in the treatment of lung cancer, the current therapeutic interventions are only partially effective, necessitating the continued search for better, novel alternative treatments. Angiogenesis and cancer stem cells play a central role in the initiation and propagation of cancers. Tumor angiogenesis is triggered by an angiogenic switch when pro-angiogenic factors exceed anti-angiogenic components. Although many anti-angiogenic agents are used in cancer treatment, there are therapeutic limitations with significant side effects.

In recent years, cannabinoids have been investigated extensively for their potential anti-neoplastic effects. Our previous findings showed that cannabidiol (CBD) could impede tumor growth in mouse models of melanoma and glioblastoma.

Importantly, CBD has been suggested to possess anti-angiogenic activity.

In this study, we tested, for the first time, inhalant CBD in the treatment of heterotopic lung cancer and whether such potential effects could reduce cancer stem cell numbers and inhibit tumor angiogenesis.

We implanted NCI H1437 human lung cancer cells in nude mice and treated the mice with inhalant CBD or placebo. The outcomes were measured by tumor size and imaging, as well as by immunohistochemistry and flow cytometric analysis for CD44, VEGF, and P-selectin.

Our findings showed that CBD decreased tumor growth rate and suppressed expression of CD44 and the angiogenic factors VEGF and P-selectin.

These results suggest, for the first time, that inhalant CBD can impede lung cancer growth by suppressing CD44 and angiogenesis.”

https://pubmed.ncbi.nlm.nih.gov/36737540/

https://link.springer.com/article/10.1007/s13577-023-00869-8