Platinum (IV) drugs with cannabidiol inducing mitochondrial dysfunction and synergistically enhancing anti-tumor effects

Chemotherapy resistance is an insurmountable problem in clinical anticancer therapy. Although Oxaliplatin is an effective chemotherapeutic agent for the treatment of colorectal cancer (CRC), it still suffers from serious toxicities as well as drug resistance. In this work, three Oxaliplatin tetravalent platinum prodrugs(O1-O3) and three novel mixed ammine/amine analogs(C1-C3) were constructed, introducing cannabidiol with anti-tumor activity in their axial position. All Pt(IV) prodrugs exhibited potent antitumor effects in a variety of tumor cell lines, especially in HCT-116 cells, where complex O3 showed strong inhibitory effects with the half maximal inhibitory concentrations (IC50) value of 6.02 ± 0.69 μM and about 2.6 times higher than that of Oxaliplatin. Further studies revealed that complex O3 decreased cellular mitochondrial membrane potential in a concentration-dependent manner and enhanced reactive oxygen species (ROS) accumulation by decreasing the expression of catalase, superoxide dismutase 2 (SOD2) and superoxide dismutase 3 (SOD3). Complex O3 induces mitochondrial dysfunction and upregulates the pro-apoptotic protein Noxa, ultimately leading to severe DNA damage. The upregulation of Phosphorylated histone protein H2AX (γ-H2AX) expression is clear evidence. In addition, O3 inhibits the expression of RAD51 protein and prevents DNA damage repair, thus overcoming drug resistance. This strategy of combining bioactive molecules cannabidiol with platinum drugs to improve therapeutic efficacy and overcome drug resistance has been proven to be very effective and deserves further investigation. Novel Pt(IV) complex O3 induces mitochondrial dysfunction and enhances ROS accumulation by decreasing the expression of catalase and Superoxide dismutase (SOD). In addition, it leads to severe DNA damage by regulating the expression of the pro-apoptotic proteins Noxa, γ-H2AX, and RAD51. [Display omitted] •The cannabidiol was introduced into the platinum antitumor drugs, and the Pt(IV) complexes O1-O3 and C1- C3 were synthesized.•Complex O3 is highly cytotoxic to all cancer cells and cannabidiol exerts a synergistic antitumor effect with Oxaliplatin.•Complex O3 causes DNA damage and inhibits DNA damage repair in colon cancer, inhibiting drug resistance.•The complex induces cell death through mitochondrial dysfunction and overexpression of the pro-apoptotic protein Noxa.