Roles and therapeutic targeting of ceramide metabolism in cancer.

BACKGROUND: Ceramides are sphingolipids that act as signaling molecules involved in regulating cellular processes including apoptosis, proliferation, and metabolism. Deregulation of ceramide metabolism contributes to cancer development and progression. Therefore, regulation of ceramide levels in cancer cells is being explored as a new approach for cancer therapy. SCOPE OF THE REVIEW: This review discusses the multiple roles of ceramides in cancer cells and strategies to modulate ceramide levels for cancer therapy. Ceramides attenuate cell survival signaling and metabolic pathways, while activating apoptotic mechanisms, making them tumor-suppressive. Approaches to increase ceramide levels in cancer cells include using synthetic analogs, inhibiting ceramide degradation, and activating ceramide synthesis. We also highlight combination therapies such as use of ceramide modulators with chemotherapies, immunotherapies, apoptosis inducers, and anti-angiogenics, which offer synergistic antitumor effects. Additionally, we also describe ongoing clinical trials evaluating ceramide nanoliposomes and analogs. Finally, we discuss the challenges of these therapeutic approaches including the complexity of ceramide metabolism, targeted delivery, cancer heterogeneity, resistance mechanisms, and long-term safety. MAJOR CONCLUSIONS: Ceramide-based therapy is a potentially promising approach for cancer therapy. However, overcoming hurdles in pharmacokinetics, specificity, and resistance is needed to optimize its efficacy and safety. This requires comprehensive preclinical/clinical studies into ceramide signaling, formulations, and combination therapies. Ceramide modulation offers opportunities for developing novel cancer treatments, but a deeper understanding of ceramide biology is vital to advance its clinical applications.

Anti-cancer effectiveness of a novel ceramide analog on chemo-sensitive and chemo-resistant breast cancers.

INTRODUCTION: Ceramides are known to show anti-cancer activity. A novel ceramide analog, (S,E)-3-hydroxy-2-(2-hydroxybenzylidene)amino-N-tetradecylpropanamide (analog 315) was developed as part of a larger study focused on finding more effective breast cancer treatments. OBJECTIVE: To assess whether analog 315 shows any or a combination of the following effects in breast cancer cells in vitro: inhibiting proliferation, inducing apoptosis, and altering protein expression. Also, to determine whether it inhibits chemo-resistant breast cancer tumor growth in vivo mouse model. METHODS: In vitro cell proliferation and apoptosis after treatment with analog 315 were assessed in three breast cancer cell lines (MCF-7, MCF-7TN-R, and MDA-MB-231) and reported. Protein expression was assessed by microarray assay. For the in vivo studies, chemo-resistant breast cancer cells were used for tumor development in two groups of mice (treated and control). Analog 315 (25 mg/kg/day) or control (dimethyl sulfoxide) was administered intraperitoneally for 7 days. Effects of analog 315 on inhibiting the growth of chemo-resistant breast cancer tumors after treatment are reported. RESULTS: Analog 315 reduced MCF-7TN-R chemo-resistant tumor burden (volume and weight) in mice. Liver metastasis was observed in control mice, but not in the treated animals. Ki-67, a proliferation marker for breast cancer cells, increased significantly ( P  < 0.05) in control tumor tissue. In vitro studies showed that analog 315 inhibited cell proliferation, altered protein expression and induced apoptosis in all three breast cancer cell lines studied, of which the effects on MCF-7TN-R cells were the most significant. CONCLUSION: Analog 315 reduced tumor growth in chemo-resistant breast cancer, inhibited cell proliferation, altered protein expression, and induced apoptosis in all three cell lines studied.

Study of Ceramide-Flavone Analogs Showing Self-Fluorescence and Anti-Proliferation Activities.

Background: Many current anti-cancer drugs used to treat breast cancer mediate tumor cell death through the induction of apoptosis. Cancer cells, however, often acquire multidrug-resistance following prolonged exposure to chemotherapeutics. Consequently, molecular pathways involved in tumor cell proliferation have become potential targets for pharmacological intervention. Ceramides are tumor suppressor lipids naturally found in the cell membrane, and are central molecules in the sphingolipid signalling pathway. Methods: Our lab has targeted the ceramide signaling pathway for potential pharmacological intervention in the treatment of breast cancer. Previously, we have shown that certain ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and multidrug-resistant breast cancers. Using the most active analog from our previous studies as the lead compound, new analogs containing a flavone moiety were designed and synthesized. In general, flavone derivatives often show interesting pharmacological properties, and compounds based on these molecules have been found useful in many different therapeutic areas including anti-tumor, anti-coagulants, and anti-HIV therapy. Results: Synthesis and biological evaluation of five new flavonoid ceramide analogs are reported here. These compounds were also shown to be self-fluorescent, which can be useful when investigating their distribution and action in cancer cells. Conclusion: Four out of the five flavone ceramide analogs in this study showed significant anti-proliferation activities in the three cell lines studied, MDA-MB-232, MCF-7, and MCF-7TN-R; some showing varying degrees of selectivity. The mechanisms involved in cell proliferation inhibition are complicated and further studies are needed.

Acute toxicity evaluation of a novel ceramide analog for the treatment of breast cancer.

We have previously reported that treating triple-negative tumor bearing nude mice with intraperitoneal (ip) 10 mg/kg body weight of (S,E)-3-hydroxy-2-(2-hydroxybenzylidene)amino-N-tetradecylpropanamide, a ceramide analog, 5 days per week for 3 weeks, was shown not only to suppress tumor growth but also to reduce metastasis. Studies reported here focus on determining the toxicity of this drug in the nude mice. During the first study, treated animals (single intraperitoneal (ip) injection, 0, 40, 80 and 120 mg/kg body weight) were closely monitored for 14 days for any signs of illness or death. No mice were lost in any animal groups; however, hepatic serum enzymes were elevated, and hepatic and heart tissue damages were found in the highest dosage group. The subsequent study was performed using a lower dosage range (single ip injection, 0, 25, 50 and 75 mg/kg body weight), which resulted in no significant toxicity. All tested parameters were within normal ranges, with no observed irregularities. Our findings show that a single ip dose of this ceramide analog induced liver and heart toxicity at 120 mg/kg but not at doses of 80 mg/kg body weight or lower.