Anticancer Potential of Cannabidiol in Renal Cell Carcinoma: Serum Modulation and Preliminary Mechanistic Insights

<b>Background</b>: Cannabidiol (CBD), the major non-psychotropic cannabinoid derived from <i>Cannabis sativa</i> L., has demonstrated broad anticancer activity across multiple tumor types; however, its effects in renal cell carcinoma (RCC) remain largely undefined. Given the ongoing need for novel therapeutic strategies in RCC, this study provides preliminary mechanistic insights into the cytotoxic, antiproliferative, and redox-modulating properties of CBD in RCC cells and evaluates the influence of serum conditions on its activity. <b>Methods</b>: Human RCC cell lines (Caki-1 and 769-P) and non-tumoral proximal tubular epithelial cells (HK-2) were treated with CBD (1-100 µM) for up to 48 h under serum-free and serum-supplemented (5%) conditions. Cytotoxic and antiproliferative effects were assessed using the MTT assay, and intracellular reactive oxygen/nitrogen species (ROS/RNS) levels were quantified using the H₂DCFDA fluorescence assay. <b>Results</b>: CBD significantly decreased RCC cell viability and proliferation in a concentration-dependent manner and induced time-dependent ROS/RNS accumulation. Comparable sensitivity was observed in non-tumoral HK-2 renal epithelial cells, indicating limited tumor selectivity under the tested in vitro conditions. Notably, these effects were markedly attenuated in the presence of serum, consistent with CBD's high serum-protein binding and reduced free bioavailability. <b>Conclusions</b>: CBD induces cytotoxic, antiproliferative, and redox-modulating effects in RCC cells in vitro; however, these responses are strongly attenuated by serum, lack tumor selectivity, and require concentrations exceeding clinically achievable plasma levels. Together, these findings delineate major translational limitations for the therapeutic use of CBD in RCC.