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Developing new ceramide analogs against non-small cell lung cancer (NSCLC)
Lu Dai1, Navneet Goyal2, Jiawang Liu3
1Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences 4301 W. Markham St., Little Rock, AR 72205, USA.
Abstract:
Non-small cell lung cancer (NSCLC) constitutes the predominant form of lung cancer and stands as the leading cause of cancer-related mortality in the United States. Conventional chemotherapy and radiotherapy yield suboptimal responses in a significant portion of lung cancer patients, resulting in a discouraging 5-year survival rate of approximately 15%. Despite advancements in targeted therapy and immunotherapy, many NSCLC patients exhibit either negligible or partial responses, emphasizing the pressing necessity for the discovery of innovative anti-cancer agents. Our previous study demonstrated that ABC294640, an inhibitor of one of the key enzymes in sphingolipid metabolism, sphingosine kinase 2 (SphK2), displayed anti-NSCLC activities in vitro and in vivo. In the current study, through the screening of a series of newly synthesized ceramide analogs, we have identified new compounds, particularly analogs 403 and 953, that exhibit potent anti-NSCLC activities. These compounds induce significant NSCLC apoptosis by elevating intracellular pre-apoptotic ceramide and dihydro(dh)-ceramide production. Lipidomics analyses further elucidate the alterations in ceramide and dh-ceramide species signature/proportion across different NSCLC cell-lines induced by these novel ceramide analogs. Treatments with ceramide analogs 403 and 953 remarkably inhibit NSCLC progression in vivo without observable toxicity. Collectively, these findings establish a foundation for the development of promising sphingolipid-based therapies aimed at enhancing the prognosis of NSCLC.
Insights
New ceramide analogs, 403 and 953, show potent anti-cancer activity against non-small cell lung cancer (NSCLC). These sphingolipid-based compounds effectively induce apoptosis and inhibit tumor progression in vivo with no observed toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality with limited treatment efficacy.
- Conventional therapies and current targeted/immunotherapies show suboptimal responses in many NSCLC patients.
- Sphingolipid metabolism, particularly sphingosine kinase 2 (SphK2) inhibition, has shown prior promise in preclinical NSCLC models.
Purpose of the Study:
- To identify novel anti-NSCLC agents through screening of synthetic ceramide analogs.
- To investigate the mechanism of action of promising ceramide analogs in NSCLC.
- To evaluate the efficacy and toxicity of novel ceramide analogs in preclinical NSCLC models.
Main Methods:
- Screening of newly synthesized ceramide analogs for anti-NSCLC activity.
- Assessment of NSCLC apoptosis induction via measurement of intracellular ceramide and dihydroceramide.
- Lipidomics analysis to characterize ceramide and dihydroceramide species alterations.
- In vivo efficacy and toxicity studies in NSCLC models.
Main Results:
- Ceramide analogs 403 and 953 demonstrated potent anti-NSCLC activity.
- These compounds induced significant NSCLC apoptosis by increasing intracellular pre-apoptotic ceramide and dihydroceramide.
- Lipidomics confirmed distinct ceramide and dihydroceramide profiles induced by the analogs.
- Analogs 403 and 953 inhibited NSCLC progression in vivo without observable toxicity.
Conclusions:
- Novel ceramide analogs 403 and 953 are effective in targeting NSCLC.
- These compounds represent a promising new class of sphingolipid-based therapeutics for NSCLC.
- Further development of these analogs could significantly improve NSCLC patient outcomes.
