Synthetic sphingolipid analogs and anti-cancer drugs synergistically induced human colon and pancreatic cancer cell death through inhibiting ceramide metabolism

Ceramide metabolism is a potential target for anti-cancer therapy. Studies show that chemotherapeutic agents can induce apoptosis and it is mediated by ceramide. Synthesized sphingolipid analogs can induce cell death in human lymphocytes and leukemia cells. By screening a group of synthetic sphingolipid analogs, we found that low concentrations of AD2750 and AD2646 induced cell death in human cancer cells by preventing ceramide from converting to sphingomyelin, individually or in combination with commercial cancer drugs. The combination of low concentrations of Taxol and AD2750 or AD2646 significantly increased cell death on human colon cancer cells (HT29). Co-administering low concentrations of Doxorubicin with AD2750 or AD2646 elevated cellular toxicity on human pancreatic cancer cells (CRL1687). This synergistic effect is related to the elevated cellular ceramide. Combining AD2750 or AD2646 with chemotherapy drugs can be used to manipulate ceramide and sphingomyelin metabolism, potentially to affect the growth of human cancer cells and increase the effectiveness of anti-cancer drugs on killing cancer cells.

Synthetic Sphingolipid Analogs and Anti-cancer Drugs Synergistically Induced Human Colon and Pancreatic Cancer Cell Death Through Inhibiting Ceramide Metabolism

Ceramide metabolism is a potential target for anti-cancer therapy. Studies show that chemotherapeutic agents can induce apoptosis and it is mediated by ceramide. Synthesized sphingolipid analogs can induce cell death in human lymphocytes and leukemia cells. By screening a group of synthetic sphingolipid analogs, we found that low concentrations of AD2750 and AD2646 induced cell death in human cancer cells by preventing ceramide from converting to sphingomyelin, individually or in combination with commercial cancer drugs. The combination of low concentrations of Taxol and AD2750 or AD2646 significantly increased cell death on human colon cancer cells (HT29). Co-administering low concentrations of Doxorubicin with AD2750 or AD2646 elevated cellular toxicity on human pancreatic cancer cells (CRL1687). This synergistic effect is related to the elevated cellular ceramide. Combining AD2750 or AD2646 with chemotherapy drugs can be used to manipulate ceramide and sphingomyelin metabolism, potentially to affect the growth of human cancer cells and increase the effectiveness of anti-cancer drugs on killing cancer cells.

C16-Ceramide Analog Combined with Pc 4 Photodynamic Therapy Evokes Enhanced Total Ceramide Accumulation, Promotion of DEVDase Activation in the Absence of Apoptosis, and Augmented Overall Cell Killing

Because of the failure of single modality approaches, combination therapy for cancer treatment is a promising alternative. Sphingolipid analogs, with or without anticancer drugs, can improve tumor response. C16-pyridinium ceramide analog LCL30, was used in combination with photodynamic therapy (PDT), an anticancer treatment modality, to test the hypothesis that the combined treatment will trigger changes in the sphingolipid profile and promote cell death. Using SCCVII mouse squamous carcinoma cells, and the silicone phthalocyanine Pc 4 for PDT, we showed that combining PDT with LCL30 (PDT/LCL30) was more effective than individual treatments in raising global ceramide levels, as well as in reducing dihydrosphingosine levels. Unlike LCL30, PDT, alone or combined, increased total dihydroceramide levels. Sphingosine levels were unaffected by LCL30, but were abolished after PDT or the combination. LCL30-triggered rise in sphingosine-1-phosphate was reversed post-PDT or the combination. DEVDase activation was evoked after PDT or LCL30, and was promoted post- PDT/LCL30. Neither mitochondrial depolarization nor apoptosis were observed after any of the treatments. Notably, treatment with the combination resulted in augmented overall cell killing. Our data demonstrate that treatment with PDT/LCL30 leads to enhanced global ceramide levels and DEVDase activation in the absence of apoptosis, and promotion of total cell killing.