Phospholipids and cholesterol: Inducers of cancer multidrug resistance and therapeutic targets

Kopecka, Joanna; Trouillas, Patrick; Gašparović, Ana Čipak; Gazzano, Elena; Assaraf, Yehuda G.; Riganti, Chiara

doi:10.1016/j.drup.2019.100670

Cited by 194 publications

(156 citation statements)

References 217 publications

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“…Among many others, one of the causes of MDR is the decreased free diffusion of anticancer drugs through the plasma membrane. Therefore, the study and development of anticancer drugs capable to exert therapeutic effect by modulating the properties of tumor membranes, is constantly increasing ( Rios-Marco et al, 2017 ; Zalba and Ten Hagen, 2017 ; Kopecka et al, 2020 ). The rationale for MLT is that there are fundamental differences in composition between normal and MDR cancer cells ( Figure 1 ).…”

Section: Mlt For Cancer Therapy: a Brief Outlinementioning

confidence: 99%

New Insights Into Targeting Membrane Lipids for Cancer Therapy

Preta

2020

Front. Cell Dev. Biol.

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Modulation of membrane lipid composition and organization is currently developing as an effective therapeutic strategy against a wide range of diseases, including cancer. This field, known as membrane-lipid therapy, has risen from new discoveries on the complex organization of lipids and between lipids and proteins in the plasma membranes. Membrane microdomains present in the membrane of all eukaryotic cells, known as lipid rafts, have been recognized as an important concentrating platform for protein receptors involved in the regulation of intracellular signaling, apoptosis, redox balance and immune response. The difference in lipid composition between the cellular membranes of healthy cells and tumor cells allows for the development of novel therapies based on targeting membrane lipids in cancer cells to increase sensitivity to chemotherapeutic agents and consequently defeat multidrug resistance. In the current manuscript strategies based on influencing cholesterol/sphingolipids content will be presented together with innovative ones, more focused in changing biophysical properties of the membrane bilayer without affecting the composition of its constituents.

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Section: Mlt For Cancer Therapy: a Brief Outlinementioning

confidence: 99%

New Insights Into Targeting Membrane Lipids for Cancer Therapy

Preta

2020

Front. Cell Dev. Biol.

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“…[1] Recently,e merginge vidence suggestst hat lipids regulatet he expression and activity of multidrug efflux pumps in cancer cells, thus contributing to the multidrug resistance (MDR)o fc ells. [2] MDR cells exhibit unique features, including the alteredc omposition of phospholipids and glycosphingolipids in plasma membrane [3] or membranes of intracellular organelles (e.g.,e ndoplasmicr eticulum (ER) and mitochondria, and Golgi apparatus), [4] the high ratio of monounsaturated/polyunsaturated fatty acid, [5] and highlyp roduced precursors of phospholipids and cholesterol. [6] All these features confer the emergence of MDR in cancer cells, which have stimulated the efforts for targetingl ipids of MDR cells.…”

mentioning

confidence: 99%

Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells

Wang

Tan

et al. 2020

Chemistry A European J

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Although lipids contributet oc ancerd rug resistance, it is challenging to target diverse range of lipids. Here, we show enzymatically inserting exceedingly simple synthetic lipidsi nto membranes for increasingm embrane tensiona nd selectively inhibiting drug resistant cancer cells. The lipid,f ormed by conjugating dodecylaminetodphosphotyrosine, self-assembles to form micelles. Enzymatic dephosphorylation of the micelles inserts the lipids into membranes and increases membrane tension. The micellese ffectively inhibit ad rug resistant glioblastoma cell (T98G) or at riple-negative breast cancerc ell (HCC1937), without inducing acquired drug resistance. Moreover,t he enzymatic reaction of the micelles promotes the accumulation of the lipids in the membranes of subcellular organelles (e.g.,e ndoplasmic reticulum (ER), Golgi, and mitochondria), thus activating multiple regulated cell death pathways. This work, in which for the first time membrane tension is increased to inhibitc ancer cells, illustratesanew and powerful supramolecular approach for antagonizingd ifficultdrug targets.

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“…HCC is a tumor type with a well-known susceptibility to mutate under selective pressure, such as that exerted by anti-cancer drugs. This implies an associated drug resistance based on a plethora of mechanisms [ 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 ]. One of the peculiar features of cancer is the metabolic reprogramming [ 7 , 219 , 220 , 221 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies

Mossenta

Busato

et al. 2020

Cancers

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Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid–lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.

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Phospholipids and cholesterol: Inducers of cancer multidrug resistance and therapeutic targets

Cited by 194 publications

References 217 publications

New Insights Into Targeting Membrane Lipids for Cancer Therapy

New Insights Into Targeting Membrane Lipids for Cancer Therapy

Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells

Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies

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