Cannabinoids, a class of compounds derived from Cannabis sativa L., have recently become more widely accessible for public consumption in the form of diverse cannabis products, in parallel with weakening the measures that so far restricted their availability. The US Food and Drug Administration has approved several cannabis-derived drugs for management of various diseases as well as chemotherapy-induced nausea and vomiting. Besides the attenuation of adverse effects of chemotherapy, numerous reports about cannabinoid-mediated anticancer effects further motivate cancer patients to support their therapy with such products. Here we present a set of preclinical data with human cell culture models, suggesting that cannabidiol and cannabis extracts may effectively counteract the anticancer effects of the clinically widely used standard-of-care platinum-based drugs. We show that even low concentrations of cannabinoids reduced the toxicity of cisplatin, oxaliplatin, and carboplatin, an effect which was accompanied by decreased platinum adduct formation and a set of commonly used molecular markers. Mechanistically, our results excluded the possibility that the observed enhanced survival of cancer cells was mediated transcriptionally. Instead, trace metal analyses strongly indicate an inhibitory impact of cannabinoids on intracellular platinum accumulation, thereby implicating changes in cellular transport and/or retention of these drugs as the likely cause of the observed biological effects. Our study raises the possibility that the desirable effect of counteracting adverse effects of chemotherapy might, at least for some cannabinoids, reflect impaired cellular availability, and consequently attenuation of the anticancer effects of platinum drugs. DATA AVAILABILITY: All data supporting the conclusions are available in the article and supplementary files. Raw data are available upon request from the corresponding author.

Centre of the Region Haná for Biotechnological and Agricultural Research Department of Genetic Resources for Vegetables Medicinal and Special Plants Crop Research Institute Olomouc Czech Republic

Czech Advanced Technology and Research Institute Palacký University Olomouc Czech Republic

Danish Cancer Society Research Center DK 2100 Copenhagen Denmark

Department of Analytical Chemistry Faculty of Science Palacký University Olomouc 17 listopadu 12 771 46 Olomouc Czech Republic

Division of Genome Biology Department of Medical Biochemistry and Biophysics Science for Life Laboratory Karolinska Institute 171 77 Stockholm Sweden

Faculty of Medicine and Dentistry Institute of Molecular and Translational Medicine Palacký University Olomouc Czech Republic

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