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.

Diterpenoids inhibit ox-LDL-induced foam cell formation in RAW264.7 cells by promoting ABCA1 mediated cholesterol efflux.

Introduction: Atherosclerosis is the main cause of many cardiovascular diseases and contributes to morbidity and mortality worldwide. The formation of macrophage-derived foam cells plays a critical role in the early stage of atherosclerosis pathogenesis. Diterpenoids found in the flowers of Callicarpa rubella Lindl., a traditional Chinese medicine, have been reported to have anti-inflammatory activity. However, little is known about the effects of these diterpenoids on macrophage foam cell formation. Methods: A macrophage-derived foam cell formation model was established by treating RAW264.7 cells with oxidized low-density lipoprotein (ox-LDL) for 24 h. Oil red O staining were used to detect the intracellular lipids. The cholesterol efflux capacity was assayed by labeling cells with 22-NBD-cholesterol. Western blots and real-time PCRs were performed to quantify protein and mRNA expressions. Results: Two diterpenoid molecules, 14α-hydroxyisopimaric acid (C069002) and isopimaric acid (C069004), extracted from the flowers of Callicarpa rubella Lindl., significantly attenuated ox-LDL-induced foam cell formation in RAW264.7 macrophages. Further investigation showed that these two diterpenoids could promote cholesterol efflux from RAW264.7 macrophages to apolipoprotein A-I or high-density lipoproteins, which was associated with upregulated expression of ATP-binding cassette A1/G1 (ABCA1/G1), liver X receptor-α (LXRα), and peroxisome proliferator-activated receptor-γ (PPARγ). Unexpectedly, the diterpenoids C069002 and C069004 failed to enhance the mRNA transcription of the ABCG1 gene in macrophage-derived foam cells induced by ox-LDL. To evaluate the effects of diterpenoids on macrophage foam cell formation and determine the underlying mechanism, two drugs (lovastatin and rosiglitazone) were used as positive controls. Although both drugs could reduce macrophage foam cell formation and promote cholesterol efflux, they each had distinctive abilities to modulate the expression of cholesterol efflux-related genes. In contrast to lovastatin, rosiglitazone showed a similar influence on the expression of cholesterol efflux-related genes (including ABCA1, LXRα, and PPARγ) as the diterpenoids regardless of the presence or absence of ox-LDL, implying a similar mechanism by which they may exert atheroprotective effects. Conclusion: Our research indicates that diterpenoids effectively inhibit ox-LDL-induced macrophage foam cell formation by promoting cholesterol efflux from macrophages via the PPARγ-LXRα-ABCA1 pathway. Further investigation of diterpenoids as potential drugs for the treatment of atherosclerosis is warranted.