Novel Agents Targeting Bioactive Sphingolipids for the Treatment of Cancer

Abstract

Sphingolipids are a class of lipids that have important functions in a variety of cellular processes such as, differentiation, proliferation, senescence, apoptosis and chemotherapeutic resistance. The most widely studied bioactive shingolipids include ceramides, dihydroceramide (dhCer), ceramide-1-phosphate (C1P), glucosyl-ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P). Although the length of fatty acid chain affects the physiological role, ceramides and sphingosine are known to induce apoptosis whereas C1P, S1P and GluCer induce proliferation of cells, which causes the development of chemoresistance. Previous studies have implicated the significance of bioactive shingolipids in oncogenesis, cancer progression and drug-and radiation-resistance. Therefore, targeting the elements of sphingolipid metabolism appears important for the development of novel therapeutics or to increase the effectiveness of the current treatment strategies. Some approaches involve the development of synthetic ceramide analogs, small molecule inhibitors of enzymes such as sphingosine kinase, acid ceramidase or ceramide synthase that catalyze ceramide catabolism or its conversion to various molecular species and S1P receptor antagonists. These approaches mainly aim to up-regulate the levels of apoptotic shingolipids while the proliferative ones are down-regulated, or to directly deliver cytotoxic sphingolipids like short-chain ceramide analogs to tumor cells. It is suggested that a combination therapy with conventional cytotoxic approaches while preventing the conversion of ceramide to S1P and consequently increasing the ceramide levels would be more beneficial. This review compiles the current knowledge about sphingolipids, and mainly focuses on novel agents modulating sphingolipid pathways that represent recent therapeutic strategies for the treatment of cancer.

Resveratrol ve Seramid Metabolizması Enzim İnhibitörleri İle Kombinasyonlarının FLT3 Pozitif Akut Miyeloid Lösemideki Sitotoksik Etkileri

“…The results indicated a time and dose-dependent decreases in cell proliferation in response to resveratrol (Figure 1A and Figure 1B) and resveratrol induced apoptosis by causing increases in apoptotic cell population in both cell lines by PS externalization (Figure 2A and 2B). As shown in many cancer types, one of the common mechanisms of resveratrol"s action is to induce apoptosis through PS relocalization shown in human melanoma cells (Zhao et al, 2018), 232B4 chronic lymphocytic leukemia (Adan-Gokbulut et al, 2013) and ovarian cancer cells (Baribeau et al, 2014). Therefore, our results are in accordance with the literatüre and resveratrol might have therapeutic effect on FLT3 positive AML cells.…”

“…On the other hand, the conversion of Cer into S1P by sphingosine kinase (SK) or/and into GC by glucosyl ceramide synthase (GCS) induces the proliferation of cancer cells (Giussani et al, 2014). Since Cer metabolism determines the cell fate which is called "sphingolipid rheostat" (Adan-Gokbulut et al, 2013), the enzymes regulating various steps of sphingolipid metabolism have been considered as potential biomarkers and chemotherapeutic targets in various malignancies (Kroll et al, 2020). Therefore, it is also important to elucidate their roles in FLT3 positive AML pathogenesis and therapy.…”

DNA Related Enzymes as Molecular Targets for Antiviral and Antitumoral Chemotherapy. A Natural Overview of the Current Perspectives

“…Plants have a long history of use in the treatment of cancer. Scientists have identified many molecules with anticancer activities from nature, including taxol, vinblastine, camptothecin, paclitaxel, cephalotaxine, matrine, and colchicine [1][2][3][4]. Chemotherapy remains to be the standard treatment for initial or advanced stages of cancer.…”