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Anti-cancer agents in medicinal chemistry [journal]
- Glycosidated phospholipids - a promising group of anti-tumour lipids. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):607-17.
Synthetic alkylphospholipids (APLs), exhibit similarity to the platelet-activating factor (PAF). These compounds have antiproliferative effects on tumour cells and can therefore be regarded as a new class of drugs. Unlike classic cytostatic agents, synthetic alkylphospholipids do not interfere with the DNA or the mitotic spindle apparatus. Instead, due to their aliphatic character, alkylphospholipids accumulate in cell membranes, where they have an impact on lipid metabolism and lipid-dependent signalling pathways which leads to inhibition of proliferation and induction of apoptosis in malignant cells. Normal cells remain unaffected by these compounds. Glycosidated phospholipids, are a novel class of alkylphospholipids, in which carbohydrates or carbohydrate-related molecules are introduced in the chemical lead of PAF. These hybrid alkylphospholipids also exhibit anti-proliferative capacity. Furthermore, members of this subfamily also modulate cell adhesion, differentiation, apoptosis and migration of tumour cells. Among the members of this group, Inositol-C2-platelet-activating factor (Ino-C2-PAF) is the most effective compound developed so far. Recently, we also showed that Ino-C2-PAF exhibited the strongest impact on the gene expression levels of immortalised keratinocytes in comparison to edelfosine and another glycosidated alkylphospholipid, Glucose-platelet-activating factor (Glc-PAF). Furthermore, Ino-C2-PAF reduced the expression of genes encoding proteins associated with inflammation and the innate and acquired immune responses.
- A Fluorescent Alkyllysophospholipid Analog Exhibits Selective Cytotoxicity Against the Hormone-Insensitive Prostate Cancer Cell Line PC3. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):528-38.
A fluorescent analog of ET-18-OCH3, 1-O-(7'-N,N-dimethylamino-3'-pentadecanoyl-1'-naphthyl)-2-O-methyl-sn-glycerophosphocholine (1), was synthesized and its bioactivity was screened against 12 human cancer cell lines. The bioactivity of 1 was found to differ markedly from that of ET-18-OCH3. Growth of two prostate cell lines (PC3 and DU145) and a glioma cell line (U251) was significantly affected by 1, with IC50 values of 2, 6, and 12 µM, respectively. Compound 1 was cytotoxic to PC3 cells by caspasedependent apoptosis. The subcellular distribution of 1 differed from that reported for a phenyl-polyene analog of ET-18-OCH3; 1 was found to be localized in the endoplasmic reticulum, mitochondria, and lysosomes but not in the plasma membrane or nucleus of PC3 cells. However, no differences in accumulation of 1 were found between PC3 and cells that were not affected by the compound, implying that the selective PC3 cytotoxicity is a consequence of specific molecular components of PC3 cells.
- Combining Anti-tumor Alkyl-Phospholipid Analogs and Radiotherapy: Rationale and Clinical Outlook. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):618-28.
Our improved understanding of the molecular processes that determine cellular sensitivity to ionizing radiation has accelerated the identification of new targets for intervention. Indeed, novel agents have become available for combined clinical use to overcome radioresistance and increase the therapeutic ratio of radiotherapy. Synthetic alkyl-phospholipid analogs (APLs), such as edelfosine, ilmofosine, miltefosine, perifosine and erucylphosphocholine, are a novel class of anti-tumor agents that target cell membranes to induce growth arrest and apoptosis. In addition, APLs strongly enhance the cytotoxic effect of radiation in preclinical models making these compounds attractive candidates as clinical radiosensitizers. In this review, we will discuss mechanisms of action underlying the rationale to combine APLs with radiotherapy and highlight the clinical perspective of this novel combined modality treatment.
- Antitumoral alkylphospholipids alter cell lipid metabolism. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):545-58.
Alkylphospholipid (APL) analogues are promising candidates in the search for treatments for cancer. In contrast to standard chemotherapeutic drugs, these lipophilic agents target the cell membrane without interacting directly with DNA. A variety of mechanisms have been suggested to explain the actions of these compounds, which can induce apoptosis and/or cell growth arrest. In this review, we focus on recent advances in our understanding of the actions of clinically-relevant APLs, such as hexadecylphosphocholine (HePC), edelfosine, erucylphosphocholine (ErPC) and perifosine on the human hepatoma HepG2 cell line, which is commonly used for lipid metabolism studies with a special emphasis on cholesterol metabolism. One consistent finding is that HePC and other APLs cause a reduction in the biosynthesis of phosphatidylcholine (PC) by inhibiting the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CT). Our research group has been at the forefront in demonstrating that exposure to APLs affects cholesterol homeostasis in mammalian cells. Treatment with HePC, for example, causes a marked enhancement in cholesterol synthesis, which has been related to an impairment in the arrival of cholesterol at the endoplasmic reticulum (ER). In a similar way to HePC, edelfosine, ErPC and perifosine increase the de novo synthesis and uptake of cholesterol and also inhibit the arrival of plasma-membrane cholesterol at the ER, which induces a significant cholesterogenic response in these cells, involving an increase in gene expression and higher levels of several proteins related to the biosynthetic pathway and receptor-mediated uptake of cholesterol. It is generally accepted nowadays that the maintenance of a tightly controlled free-cholesterol/PC ratio is crucial to optimum cell behaviour and that alterations to this ratio may lead to necrosis and/or apoptosis. Our results have considerable bearing on this idea because an increase in cholesterol biosynthesis associated with a decrease in the synthesis of choline-containing phospholipids and cholesterol esterification leads to a modification in the free-cholesterol/PC ratio in cells exposed to APLs. It is well accepted that cholesterol is critical for the formation of lipid rafts and therefore drugs that alter cell cholesterol content should modify the properties of these membrane domains and consequently the signal-transduction pathways, which depends upon lipid-raft integrity. Results on the whole show that APLs share a common active mechanism consisting of disrupting PC and sphingomyelin (SM) biosyntheses and cholesterol homeostasis, all of which leads to a disturbance in the native membrane structure, thus affecting signaling processes vital to cell survival and growth.
- Current view on the mechanism of action of perifosine in cancer. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):629-35.
Perifosine treatment exhibits a complex molecular response including the inhibition of Akt or the induction of apoptosis via clustering of death receptors in lipid rafts. However, the molecular response can vary between different tumor entities and the contribution of each target pathway to the activity of Perifosine might be distinct depending on the tumor entity or the agent combined with Perifosine. In this review we discuss the current view on the mechanism of action of perifosine in cancer and the contribution of the molecular targets of Perifosine to its activity.
- Apoptosis Induction by Erucylphosphohomocholine via the 18 kDa Mitochondrial Translocator Protein: Implications for Cancer Treatment. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):559-77.
Many types of cancer, for example glioblastoma, show resistance against current anti-cancer treatments. One reason is that they are not capable to effectively activate their intracellular cell death pathways. Novel treatments designed to overcome these deficiencies in cancer cells present promising concepts to eradicate chemotherapy-resistant cancer cells. One of these approaches includes the membrane seeking compound erucylphosphohomocholine (ErPC3) which is part of the latest generation of alkylphospholipid analogs developed over the last two-and-a-half decades. ErPC3 exerts potent antineoplastic effects in animal models and against established cancer cell lines including, for example, glioblastoma and different types of leukemia, while sparing their normal counterparts. Starting with a historical survey, we report here on the anticancer activity of ErPC3 and on ErPC3's established mechanisms of action. We cover the current knowledge on the induction of mitochondrial apoptosis by ErPC3, including its interaction with the 18 kDa translocator protein (TSPO). In addition we discuss other signaling pathways modulated by ErPC3. Interaction with the TSPO leads to activation of the mitochondrial apoptosis cascade. This includes cardiolipin oxidation at mitochondrial levels, collapse of the mitochondrial membrane potential, and release of cytochrome c, the initiating steps of the mitochondrial apoptosis cascade. Other pathways modulated by ErPC3 include different kinases for the PI3K/Akt/mTOR and the MAP kinase pathways. Furthermore, ErPC3's cytotoxic actions may include its effects on phosphatidylcholine synthesis to inhibit the endoplasmic reticulum enzyme CTP:phosphocholine cytidyltransferase. These basic research data hopefully will lead to effective approaches toward exploitation of ErPC3 for the treatment of cancer.
- Edelfosine in membrane environment - the langmuir monolayer studies. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):499-508.
The Langmuir monolayer technique is one of the methods used to build models of cellular membranes and enables to investigate the interactions of membrane components with other biomolecules. This method has been applied to study the effect of edelfosine - a synthetic alkyl-lysophospholipid analog - on model lipid membranes in order to get insight into its mode of action and selectivity. Edelfosine is mainly known for its anticancer properties, although it is also applied in the treatment of other diseases, like autoimmune, anti-HIV and antiparasitic. In this review we focus on its antitumor activity (although some other aspects of its therapeutic effects are also indicated) and summarize the results obtained so far with use of the monolayer technique. The application of this method evidenced for a key role of cholesterol and membrane rafts in the mechanism of anticancer activity of edelfosine. As regards the selectivity of this drug, the obtained results proved that the difference in fluidity of tumor versus normal cell membrane is important but probably not the only factor determining an easier incorporation of edelfosine into cancer cells. Further studies show that edelfosine is of strong affinity to gangliosides, which may be considered as molecules targeting edelfosine into cancer cell membrane.
- Glycosylated antitumor ether lipids: activity and mechanism of action. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):592-606.
Glycosylated antitumor ether lipids (GAELs) are distinguished from the alkyllysophospholipids or alkylphosphocholines classes of antitumor ether lipids (AEL) by the presence of a sugar moiety. Non-phosphorus GAELs, the subject of this review, have a sugar moiety in place of the phosphobase found in alkyllysophospholipids. Analogues of non-phosphorus GAELs with glucose, maltose, arabinose, or disaccharide moieties have been synthesized. Non-phosphorus GAELs with monosaccharides have cytotoxic and antiproliferative effects against cancer cells derived from a wide range of tissues, including drug resistant cell lines. The most active compound of this group to date is 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol (11), which displays in vitro activity similar to or greater than that of ET-18-OCH3, the AEL "gold" standard. While the detailed molecular mechanism of action of non-phosphorus GAELs is not known, the data indicate that non-phosphorus GAELs are taken up by endocytosis and incorporated into early endosomes. The presence of non-phosphorus GAELs perturbs the maturation of the endocytic vesicles, resulting in the formation of large acidic vacuoles. Cell death appears to be the result of the release of cathepsins from the vacuoles into the cytosol and subsequent activation of a death pathway that is independent of the mitochondria and independent of apoptosis. The ability of these GAELs to kill cells via an apoptosis-independent mechanism makes them prime candidates for development of effective compounds against chemo-resistant tumors and cancer stem cells. The disaccharide-linked GAELs do not have cytotoxic activity but rather inhibit cancer cell motility due to the ability of the compounds to block specific calcium-activated potassium channels in cells. The antitumor activities displayed by these experimental compounds augurs well for their eventual development into clinically useful agents for cancer treatment.
- 1-O-Octadecyl-2-O-Methylglycero-3-phosphocholine (Edelfosine) and Cancer Cell Invasion: A Short Review. [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):539-44.
1-O-octadecyl-2-O-methylglycero-3-phosphocholine (ET-18-OMe) is an analogue of the naturally occurring 2- lysophosphatidylcholine belonging to the class of alkyllysophospholipids (ALPs). ALPs accumulate in cell membranes and can modulate phospholipid metabolism as well as signal transduction pathways, often inducing apoptosis. This review describes the effect of ET-18- OMe on cancer cell invasion. Interestingly, ET-18-OMe may inhibit invasion of cancer cells but can also stimulate invasive behavior of cancer cells. We discuss the biochemical alterations that are induced by ET-18-OMe under these circumstances and conclude that ET-18- OMe is an interesting tool to study mechanisms of tumor cell invasion since it has pointed to yet unknown aspects of these mechanisms.
- Editorial: antitumor alkylphospholipid analogs: a promising and growing family of synthetic cell membrane-targeting molecules for cancer treatment). [Journal Article]
- Anticancer Agents Med Chem 2014 May; 14(4):495-8.