Abstract
Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer therapy, this review focuses on the main enzymes implicated in sphingolipids metabolism and their intermediate metabolites involved in cancer drug resistance.
Highlights
Cancer incidence and mortality are growing fast worldwide, with a higher frequency in countries with higher socioeconomic development, as life expectancy continues to rise
Intrinsic resistance arises from the administration of Sphingolipids and Cancer Resistance chemotherapy treatment, and it is due to preexisting factors of the tumor, so the tumor cannot respond to the initial treatment
There are several mechanisms by which tumoral cells acquire this resistance to treatment: inactivation of the drug, multi-drug resistance (MDR) mechanisms, cell death inhibition increasing resistance to apoptosis, changes in cell metabolism, epigenetics modulation, increased DNA repair and gene mutation or amplification that cause the resistance to the chemotherapy [4]
Summary
Cancer incidence and mortality are growing fast worldwide, with a higher frequency in countries with higher socioeconomic development, as life expectancy continues to rise. Sphingolipids and Cancer Resistance chemotherapy treatment, and it is due to preexisting factors of the tumor, so the tumor cannot respond to the initial treatment. On the other hand, acquired resistance appears during or after the administration of treatment and is usually the main contributing factor for relapse. Some theories explain this resistance as sporadic genetic mutations maintained by Darwinian selection through the exposure to the chemotherapeutic agent [2, 3]. The enzymes involved in the sphingolipids’ metabolism have been studied during the last decade and have been directly linked to the control of cell growth, proliferation and apoptosis, among other cellular functions. This review focuses on the importance of these enzymes with a specific focus on their response to drug therapy
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