Chapter Twelve - Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era
Section snippets
Chemotherapy
Chemotherapeutic or cytotoxic agents are drugs commonly used as standard of care for multiple types of cancers due to their ability to kill or damage highly proliferative cells. These agents are usually divided into classes based on their mechanisms of action, and, strikingly, a wide range of these classes have been described as leading to accumulation of sphingolipids (particularly ceramide) in cells. As shown in Fig. 1, we depict the steady state accumulation of endogenous ceramide via chemo-
Current Landscape of Inhibitors of Sphingolipid Metabolism
Sphingolipids are vital to normal cell function and thus the dysregulation of the enzymes responsible for their production and maintenance can lead to a number of diseases, including cancer. As such, the ability to regulate the activity of these enzymes using inhibitors or activators is important for developing novel treatments for diseases in which sphingolipid imbalance occurs. Thus, the search for effective inhibitors for the enzymes that decrease ceramide levels are worth exploring. The
Methods for Delivery of Sphingolipids and Mimetics to Cells
Instead of relying on increasing “flow through the faucets or clogging the drains,” we can also simply add water to the sink externally to overflow the system (Fig. 1). Over the past 10 to 15 years, a number of approaches have been developed to enhance delivery of sphingolipids and analogues directly to cells in an effort to alter cell physiology, usually to disrupt the growth of tumor cells. Of these delivered sphingolipids, the most common is ceramide, with numerous chemical modifications and
Sphingolipids Synergize With Chemotherapeutics
Recent studies have shown that elevating endogenous levels of ceramide by opening metabolic “faucets” or closing some of the enzymatic “drains” can augment the efficacy of conventional treatments in cancer. In addition, exogenous delivery platforms for sphingolipid mimetics can also elevate endogenous ceramide levels (Fig. 1). This section will review underlying combinatorial/synergistic cytotoxic mechanisms between elevated ceramide levels/decreased S1P levels and chemotherapeutic regulation
Conclusion
In the ever-growing quest to better understand the basis of cancer, numerous tools and collaborative efforts have emerged as powerful initiatives for research and medicine. The Cancer Genome Atlas represents one of the largest such endeavors, chronicling patient samples and organizing them by cancer type, gene expression, RNA profile, and mutation profile, among others. With the increasing sensitivity and selectivity as well as availability of mass spectrometry devices capable of creating full
Acknowledgments
This work was supported by National Institutes of Health Grants 5 P01 CA171983 and R01s CA208396, CA167535 to MK; R01 GM043880 to SS.
Conflict of Interest
Penn State Research Foundation has licensed ceramide nanoliposomes and other sphingolipid-based nanoscale therapeutics to Keystone Nano, Inc (State College, PA). MK is Chief Medical Officer and cofounder of Keystone Nano, Inc.
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Cited by (45)
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miR-495–3p regulates sphingolipid metabolic reprogramming to induce Sphk1/ceramide mediated mitophagy and apoptosis in NSCLC
2022, Free Radical Biology and MedicineCitation Excerpt :Furthermore, although “sphingolipid rheostat” describes the regulatory role of ceramide and S1P in growth and survival, C2 and C6 ceramide administration displayed limited benefits in a phase-II study of cutaneous breast cancer [23]. Moreover, Sphk1 inhibitors targeting S1P production showed mixed outcomes in preclinical animal studies [24]. Collectively, these studies jolt us to evaluate the sphingolipid metabolism to identify the key nodes involved in sphingolipid metabolic reprogramming of NSCLC cells.
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Influence of ceramide on lipid domain stability studied with small-angle neutron scattering: The role of acyl chain length and unsaturation
2022, Chemistry and Physics of LipidsCitation Excerpt :Our results show that these short chain species do not provide sufficient favorable interactions to stabilize ordered phases and thus result in significant membrane disorder, with C6:0-cer being the most domain destabilizing lipid of those studied here. Several studies have shown that C6:0-cer is also the most apoptotic ceramide species, which may be a consequence of this destabilization (Brown et al., 1999; Ogretmen, 2018; Kester et al., 2015; Shaw et al., 2018). Work by Megha (2004) suggested a limited capacity of ordered phases to accommodate small-headgroup ceramide species (Megha, 2004; Ali et al., 2006).
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Identification of novel lipid metabolic biomarkers associated with poor adrenocortical carcinoma prognosis using integrated bioinformatics
2022, Surgery (United States)Citation Excerpt :These results suggest that understanding the mechanism through which sphingolipid metabolism modulates steroidogenesis either alone or in combination with current therapies could lead to novel therapeutic strategies for treating ACC patients. As therapeutics targeting sphingolipid metabolism including fingolimod inhibiting SGPL1 are already in clinical trials,28,29 preclinical evaluation of these drugs alone or in combination with current therapeutics would provide both a rationale and validation for future clinical translation for patients with advanced ACC. This research was funded in part by the National Institutes of Health (R01 CA173292 and R01 CA216919 [M.S.C. and B.S.J.B.], 3U01 CA120458 [M.S.C. and B.S.J.B.]), the University of Michigan Comprehensive Cancer Center Support Grant P30-CA-046592, and the University of Michigan Department of Surgery.
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Short asymmetric syntheses of sphinganine [(2S,3R)-2-aminooctadecane-1,3-diol] and its C(2)-epimer
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Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling
2020, iScienceCitation Excerpt :Dysregulation of sphingolipid metabolic enzymes is associated with cancer progression (Beckham et al., 2012; McNair et al., 2017; Ryland et al., 2011; Saad et al., 2007; Voelkel-Johnson et al., 2018). Moreover, ceramide accumulation in tumors is associated with cancer cell death, which emphasizes the potential role of ceramide as a cancer treatment (Grosch et al., 2012; Hannun and Obeid, 2018; Maceyka and Spiegel, 2014; Ogretmen, 2018; Shaw et al., 2018; Taha et al., 2006). De novo synthesis of ceramide and other sphingolipids is achieved by condensation of L-serine with an acyl-CoA substrate (Davis et al., 2018).
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Contributed equally.