Synergistic effect of Cannabidiol with Dasatinib on lung cancer

Dasatinib, a multi-kinase inhibitor, has demonstrated effectiveness against various solid tumors, including lung cancer, by inhibiting SRC family kinases (SFKs). However, dasatinib’s efficacy is often compromised due to off-target toxicity and the development of drug resistance. To overcome these challenges, the combination of dasatinib with Cannabidiol (CBD), a non-psychoactive cannabinoid known for its anti-cancer properties was studied. Indeed, CBD has shown potential in inhibiting cancer growth by targeting multiple pathways, such as the PI3K/AKT pathway, which promotes cancer cell survival and proliferation.

In the mouse xenograft model study, the combination of cannabidiol (CBD) and dasatinib led to a significant tumor reduction. Specifically, the tumor volume in the combination treatment group was much smaller than in the groups treated with CBD or dasatinib alone. According to the study, the combination therapy resulted in a more than 50% reduction in tumor volume compared to the control group. This marked reduction highlights the potential of the combination to enhance antitumor effects synergistically in vivo.

Key Findings

Synergistic Anti-Cancer Effects: The combination of CBD and dasatinib exhibited significant synergistic effects in vitro and in vivo on lung cancer cells. The synergy was quantified using the ZIP (Zero Interaction Potency) model, where a synergy score greater than 10 indicates likely synergistic effects. The maximum synergy score observed was 23.9, indicating a strong interaction between CBD and dasatinib. This combination significantly inhibited the proliferation and induced apoptosis in A549 lung cancer cells compared to either treatment alone.

Inhibition of Cell Migration and Invasion: CBD combined with dasatinib was effective in reducing the migration and invasion abilities of lung cancer cells. In vitro assays, including wound healing, colony formation, and transwell migration assays, demonstrated that the combination therapy significantly inhibited these processes, suggesting that the treatment could prevent cancer metastasis.

Apoptosis and Cell Cycle Arrest: The combination of CBD and dasatinib induced apoptosis in lung cancer cells by upregulating pro-apoptotic proteins, such as Bax and caspase-3, while downregulating the anti-apoptotic protein Bcl-2. Flow cytometry revealed an increase in the apoptotic cell population, with the combination treatment increasing apoptosis rates to 35.7%, compared to 10.2% and 24.6% for CBD and dasatinib alone, respectively. The combination therapy also caused cell cycle arrest in the G2/M phase, which is crucial for inhibiting cancer cell growth.

Targeting the SRC/PI3K/AKT Pathway: The study found that the combination of CBD and dasatinib targeted the SRC/PI3K/AKT signaling pathway, which plays a key role in cancer cell proliferation and survival. Western blot analysis showed that the combination treatment significantly reduced the expression of phosphorylated SRC, PI3K, and AKT proteins, effectively inhibiting this pathway and promoting apoptosis.

In Vivo Efficacy and Safety: In a xenograft mouse model of lung cancer, the combination of CBD and dasatinib demonstrated enhanced tumor suppression compared to either treatment alone. The combination treatment also showed minimal toxicity, as no significant changes in body weight or damage to major organs were observed in the treated mice.

Reference

Ye, Qianqian & Gui, Changqin & Jin, Di & Zhang, Jiazhen & Zhang, Jing & Ma, Na & Xu, Li. (2024). Synergistic effect of cannabidiol with dasatinib on lung cancer by SRC/PI3K/AKT signal pathway. Biomedicine & Pharmacotherapy. 173. 116445. 10.1016/j.biopha.2024.116445.