Review Article

Small Molecule Modulation of Lipid-Dependent Cellular Processes against Cancer: Fats on the Gunpoint

Aswin Srivatsav T, Manjari Mishra and Shobhna Kapoor*
Department of Chemistry, Indian Institute of Technology Bombay, India


*Corresponding author: Shobhna Kapoor, Department of Chemistry, Indian Institute of Technology Bombay Powai-400076, India

Published: 05 Apr, 2018
Cite this article as: Aswin Srivatsav T, Mishra M, Kapoor S. Small Molecule Modulation of Lipid- Dependent Cellular Processes against Cancer: Fats on the Gunpoint. Clin Oncol. 2018; 3: 1449.

Abstract

Lewis Thomas in the Lives of a Cell emphasized the complexity encoded by the variety of lipids and their induced structural platforms. Lipid assemblies are complicated biological constituents in that they self assemble non-covalently and create lipid bilayers, within which lipid molecules relocate in a variety of ways. The matrix of cellular membranes is formed by polar lipids, which consist of a hydrophobic and a hydrophilic portion.


Introduction

The propensity of the hydrophobic moieties to self-associate (entropically driven by water) coupled with the tendency of the hydrophilic moieties to interact with aqueous environments andin some cases-with each other, forms the physical basis of the spontaneous formation of membranes [1]. With careful cataloguing of lipids (Lipidomics) we are only beginning to comprehend the astounding diversity of lipids in the cellular membranes. The membranes in eukaryotic cells have a wide repertoire of structural lipids. The first one includes glycerophospholipids such as Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylserine (PS), Phosphatidylinositol (PI), and Phosphatidic Acid (PA) [2]. Sphingolipids constitute another class of structural lipids with their hydrophobic backbone as a ceramide moiety. The major sphingolipids in mammalian cells are sphingomyelin and glycosphingolipids. Sterols are the major non-polar lipids of cell membranes representing a unique class, due to their annealed structures that embody a highly condensed hydrophobic area. Many possible variations in the lipid’s hydrophilic head groups and hydrophobic tails add a high level of complexity to the existing vast pool of lipids. A considerable part of our genome (~5 %) continuously synthesizes and regulates this complex array of lipids, leaving some simple yet profound questions. Why is such a complex diversity of lipids maintained? Could this imply that cells are continuously trying to create heterogeneity in the membrane? Are they aiming at phase coexistence; manifested as the existence of domains of coexisting phase(s)? Many possible variations in the lipid’s hydrophilic head groups and hydrophobic tails add a high level of complexity to the existing vast pool of lipids. Steric and electrostatic interactions and hydrophobic mismatch induce phase segregation that forms distinct domains in the bilayer [3- 5]. This ability of lipid membranes to exist in a multitude of phases, characterized by a different spatial arrangement and motional freedom of each lipid with respect to its neighbors, has lead to redefining membrane functionality [6]. These phases are influenced by their molecular structure and environmental conditions like pH, ionic strength, water content, temperature, and pressure; they have long fascinated scientists in the field of membrane biophysics.
Lipids fulfill many critical requirements in the cell including composing membrane bilayer, storing energy due to their reduced state, acting as first and second messengers in signal transduction, providing functional implementations of membrane-proteins structure and function and finally recognition processes. Advanced Mass-spectroscopy and analytical techniques have allowed sensitive and highly selective analysis of lipids of diverse chemical structures within complex biological samples and testified their intimate involvement and their aberrations in many diseases such as neurodegenerative disorders, infectious diseases and cancer. Interestingly, lipidomics have revealed cancer type–specific alteration in the lipidome of cells implying critical roles of lipids in cancer progression and initiation [7-9]. Admitting, most of the drugs in the market against cancer (also diabetes and inflammation) elicit their effects via binding to their target proteins and regulating the underlying cancer-related cellular process. However in line with the increasing evidence elucidating the role of membrane lipids in regulating numerous cellular functions, they have emerged as attractive molecular targets where in therapies modulating membrane lipids structures and localization could be developed to control molecular events including changes in cell signaling, membrane protein function, localization and gene expression related to various pathological states-so called the “membrane-lipid therapy” [10,11].


Table 1

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Table 1
Small molecule inhibitors targeting lipid-related cellular pathways for cancer treatment.

Membrane Lipid Micro-Domains as the Cellular Signaling Hot Spots

High compositional complexity modulates interactions and localizations of lipids in membrane and befittingly influences the diverse phases lipid can form [12]. The same are the authors of spatially constrained distinct regions enriched in certain lipids within the membrane bilayer plane called microdomains [13,14]. One such microdomains, lipid rafts, are dynamic assemblies of cholesterol and sphingolipids predominantly in the exoplasmic leaflet of the lipid bilayer. Underpinning this concept is the propensity, in vitro; of the saturated hydrocarbon chains intercalating strongly with cholesterol molecules inducing liquid ordered lo phases [15-17]. The membrane surrounding lipid rafts is fluid-like due to the presence of unsaturated phospholipids forming the liquid disordered ld phase. Thus, the raft domains can be imagined as platforms of lo phases dispersed in the ld matrix of unsaturated glycerolipids.
These raft-like assemblies are ordered and tightly packed, but are still fluid due to packing differences. This, in turn, is governed by the saturation level of the hydrocarbon chains in the rafts compared with the unsaturated state of fatty acids of phospholipids in the ld phase.
These raft act as membrane scaffolds to house various proteins, organize receptors and their downstream molecules and hence regulate a number of membrane-associated signaling pathways [18,19]. In this regard, post translational modification of proteins such as addition of GPI anchor, acylation etc. Indispensably modulates the membrane affinities of proteins including GPI anchored proteins, epidermal growth factor receptors, and estrogen receptors etc. Membrane rafts are implicated in regulation of cell differentiation proliferation, apoptosis, necrosis as well in cancer initiation and progression [20]. Their involvement in numerous tumor models such as colon, prostrate, lung and breast has been identified but their structure, function and associated signaling pathways are still under intense scrutiny and subject of immense therapeutic interest [21-24].
On the mechanistic level, a cellular signaling event originates from the raft domains at the membranes with transmission of signals (chemical, biological and physical in nature) through membrane bound receptors e.g. Receptor Tyrosine Kinases (RTKs). Stimulation by the diverse signals promotes receptor dimerization enabling their phosphorylation mostly via their intrinsic tyrosine kinase activity. The resulting phosphorylated residues exposed to the cytoplasm act as docking sites for effect or proteins that harbor specialized membrane-loving domains—fostering their recruitment to the membrane. This chain of events induces allosteric changes in the activity and/or affinities on another module of the recruited molecule conveying signals deep into the cell and finally leading to regulation of processes like proliferation, migration, division, and differentiation among others. Malfunctioning of the cellular signaling both inherent and induced at any given step in space and time results in unchecked downstream cellular functions culminating into various diseases, especially cancer. As an example, we focus on the most fundamental signaling cascade mediating proliferation and differentiation— mitogen-activated protein kinase cascade, MAPK signaling, (Figure 1). The pathway gets activated when one of the several extra cellular ligands (e.g., epidermal growth factors, EGF) bind to the different plasma membrane-bound receptors, EGFR, leading to the dimerization and auto-phosphorylation of the cytoplasmic domain of EGFR (i.e., RTK).
EGFR stimulation promotes binding to adaptor proteins GRB2, which further binds Son of Sevenless (SOS) [25]. This binding evokes recruitment of SOS to the plasma membrane, where its close proximity to the membrane-bound small monomeric G protein, Ras, forms the prerequisite for Ras activation [26,27]. Ras proteins are membrane-associated molecular switches that lie at the heart of MAPK signaling cascade as signaling convergence modules and hold the place of the first oncogene to be discovered and yet undruggable to date [28-30].
Activated Ras initiates a series of phosphorylation (and hence activation) events of protein kinases that act as downstream effect or proteins of Ras. The most abundant effect or protein of Ras is RAF and Ras-activated RAF further activates MEK followed by ERK, which finally travels into the nucleus in its phosphorylated form to activate transcription factors leading to cell proliferation and differentiation [31]. This linear description is rather an oversimplified and abridged depiction of the complex membrane-associated Ras signaling. Misregulation of Ras signaling e.g. by virtue of failed phosphorylation events, improper membrane recruitment of effect or proteins, improper localization with raft domains or mutations account for 50 and 80% of colon and pancreatic cancers, thus emphasizing the essential role of Ras in normal cell development [32].


Aberrations of Lipids and Lipid Domains in Cancers: Tangible Targets

Pathological, pharmacological, and nutritional situations strongly regulate lipids in cell with profound biological implications. With advances in high-throughput lipidomics, precise characterization of lipid structures is revealing critical lipid alterations in composition and abundance among various cell types, cancers and surprisingly during varied cellular processes as well [7,33]. For instance, Eggert et al demonstrated nice correlation of lipidome changes with cell cycle, with up to eleven different lipid families (chemically distinct structures) accumulating in the dividing cells concluding that cells actively modulate the lipid composition and localization to specific membrane locations required for a particular cellular event [34]. Cellular lipidome remodeling in cancer is manifold and occurs at transcriptomic and lipidomic levels with intriguing complexities [35].
Lipid membranes of cancer cells possess relatively higher negative charge due to increased abundance of PS and PE phospholipids on the exoplasmic membrane surface [36,37]. On a different note, this contributes to attenuation of repulsion between polar head groups leading to denser lipid packing and concomitantly higher rigidity and poor drug penetration. Thus, exposed PE on the outer membrane of cancer cell represents a suitable molecular target to develop novel cancer therapeutics aimed at specific binding to or selective sorting of PE leading to cancer cell membrane disruption, permeabilization and finally cell death [38-40]. Cholesterol is another significantly altered molecule within lipid rafts during cancer, where in the levels are strikingly increased compared with normal cells [41,42]. Higher cholesterol leads to a more rigid and hence less permeable cell membrane [43,44]. In addition to cholesterol, other phospholipid such as PC, PI etc are also found in increased abundance in cancer cells. The most foremost effect of elevated cholesterol is higher raft formation and momentous enrichment of specific proteins and receptors such as EGFR, IGF-1, CD44, and CD24 etc involved in cellular signaling mediating tumor progression and invasion [23,45,46]. Thus strategies involved in modulation of lipid rafts are increasingly becoming enticing candidates for cancer therapy [47-49]. Down-regulation of Ceramide metabolism is another strategy found in cancer cells leading to formation of specialized membrane domains that recruit specific proteins involved in apoptosis highlighting proteins and kinases involved in ceramide metabolism as potential cancer targets [50]. In addition, a wide variety of tumors also show up-regulated transcripts involved in lipogenesis and cholesterol synthesis pathway, essential for their development and cancer progression. Lipogenic enzymes such as acetyl-CoA carboxylase and fatty acid synthase display a universal increased expression coupled with specific alterations in lipid messengers (PIs), lipid mediators (leukotrienes) and structural lipids (GSL) in most tumors [51]. In this review we will mainly focus on the small molecules that target cancer by modulating raft assembly, affecting lipid metabolism and regulating lipid sorting or lipoprotein trafficking inherent in oncogenic signaling (Table 1).


Figure 1

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Figure 1
Schematic presentation of MAPK/Ras signaling pathway. Membrane raft bound-Ras upon activation by variety of extracellular stimuli undergoes a conformational change facilitated by its membrane localization in its switch regions, which is then recognized by other downstream effect or proteins in the pathway. This enables signaling events to get amplified downstream producing distinct biological outputs raging from cell growth, differentiation, apoptosis, and vesicle transport. Any kind of alteration in Ras itself or raft membrane results in various syndromes. Adapted from S. Kapoor, Dissertation TU Dortmund (2012).

Figure 2

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Figure 2
Schematic overview of targeting lipid associated cellular functions in cancer with small molecules.

Small Molecule Chemical Biology Tools

Small molecules targeting specific biomolecules and modulating their structure and activity in vivo has transformed the field of eukaryotic cell biology. Small molecule-mediated inhibition of the function of specific proteins has enabled cell biologists to query their functional roles. Most classic example in this regard is of colchicine and paclitaxel as tubulin depolymerizes and stabilizers respectively, which have provided unprecedented insights into the function of this cytoskeletal protein [52,53]. Development of a toolbox of small molecule inhibitors against cytoskeletal proteins and many more have enabled regulation of their structure, function and localization in such ways that were difficult to achieve solely by genetic approaches. The use of chemical biology tools specifically to study lipid organization offers key advantages. (a) They act fast and their activity can be modulated as a function of dose (b) They may be reversible or not (covalent binders) (c) require no manipulation of the chromosome (d) inhibitors targeting conserved cellular processes may be applicable across a broad range of species. Due to such salient features, they have a great potential in studying the lipid domain organization in live cells, thus permitting insights into the functional role of membrane organization in cancers and other diseases [54,55].


Membrane Raft Modulating Agents in Cancer

Membrane rafts regulate key signaling molecules and proteins implicated in cancer by modulating their association with and localization with lipid membranes including interactions with other membrane-bound proteins [18,20,47,56,57]. Thus small molecule approaches aimed at interrupting the association of such molecules to membrane rafts by interfering with association steps directly or modulating the rafts themselves represents innovative therapeutic ways for prevention and treatment of cancer.


Small Molecules Acting Via Membrane Raft Disruption

Raft disruption using small molecules has been shown to cause decreased cancer cell growth, reduced cellular adhesion and inhibited migration. Among the most promising candidates are flipins, statins, Emodin and Methyl-β-cyclodextrin -MβCD Emodin, 3-methyl-1, 6,8-trihydroxyanthraquinone, inhibits cancer cell migration by mainly suppressing the PI3K-Cdc42/Rac1 signaling pathway [48,58]. Emodin markedly reduces integrin β1 clustering and its colocalization with membrane rafts as judged by cell-based microscopy assays in breast cancer model cell lines [59]. Furthermore, its mechanism of action includes suppression of translocation of integrin β1, and Focal Adhesion Complex (FAC) from cytoplasm to membrane rafts, mainly attributed to reduced cholesterol levels in the membranes, thus hampering efficient raft signaling-platform formation [60]. Thus, the inhibition of membrane raft clustering or activation of raft disruption by Emodin is the underlying mechanism leading to suppression of integrin clustering and FAC formation, and hence halting oncogenic signaling dependent on integrin. Methyl-β-cyclodextrin (MβCD), a cyclic oligosaccharide absorbs cholesterol from the cell membrane and has been shown to impair actin polymerization, cell migration, Akt phosphorylation, protein kinase C translocation and EGF-induced cell adhesion in selective cancer cell models [61,62]. Interestingly, due to the biochemical effects of MβCD, this molecule has been chemically modified to serve as platform for cellular lipid shuffling enabling generation of asymmetric model membrane systems [63-65]. Statins, the first committed inhibitors of the mevalonate pathway act at an early step in the synthesis of cholesterol [66]. The stain family consists of several drugs that are notoriously known for inhibiting oncogenic signaling in cancer cells through disintegration of membrane rafts resulting from reduced cholesterol levels [67-69]. Vastatin inhibits prostate cancer cell growth and inhibits angiogenesis and Simvastatin, another drug belonging to the statin family acts by down-regulating PI3K/Akt/Caspace-3 signaling and Fas translocation mainly by modulation of raft assembly [69,70]. Furthermore, simvastatin blocks Ras-membrane localization, and down modulates H-Ras protein at the post-translational level [71]. It also selectively dissociated latent membrane protein 1 (LMP1) from membrane rafts and reduces activation of NK-κB signaling culminating to apoptosis [72,73]. Surprisingly the small molecules belonging to the statin family, all act predominantly by remodeling membrane rafts composition and organization, however lead to distinct down-stream effects on the oncogenic signaling in various cancer models. This brings to the forefront membrane rafts as “selective cancer therapeutic targets”, with the structure, function and associated raft-signaling pathways being subject of extensive studies. As such, a better understanding of these aspects of raft biology would foster exploitation of membrane rafts for developing personalized cancer therapy for targeting distinct raft-associated oncogenic signaling in various cancers.


Small Molecules Acting by Stabilizing Membrane Domains Involved in Apoptotic Signaling

Recent studies have elucidated membrane rafts to form signaling platforms capable of activating pro- and anti-apoptotic pathways susceptible to pharmacological perturbations aimed at stabilizing these special apoptotic-linked raft domains [74]. Activation of pro-apoptotic pathways begins with activation of pro-apoptotic membrane receptor molecules via oligomerization by agents that promote raft integrity in the absence of receptor ligands. There are two major apoptotic pathways, extrinsic and intrinsic those originate from membrane rafts [75]. The extrinsic pathway is kick-started by death receptors, e.g. Fas. Following stimulation by its ligand–FasL, Fas undergoes clustering and recruits adaptor protein, Fas-associated death domain-containing protein–FADD [76]. FADD interacts with procaspace-8 forming the so-called Death-Inducing Signaling Complex (DISC) that leads to activation of downstream signaling and eventually apoptosis [77]. Activation or clustering of Fas receptor or death receptors in general is critically dependent on membrane rafts to trigger apoptotic signal transduction and is amenable to small-molecule perturbations as follows [78]. Resveratrol is shown to induce apoptosis in colon cancer cells by redistributing Fas among other death rectors in membrane rafts [79]. Avicin D, a plant triterpenoid selectively inhibits growth of tumor cells via activation of caspase pathway, i.e., regulated Fas translocation into membrane rafts and subsequently interactions with FADD and procaspcase-8 to form DISC and hence cause cell apoptosis [80]. Finally along similar lines, Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero- 3-phosphocholine)–a synthetic lipid, induces apoptotic response by accumulating in the membrane rafts and altering their lipidprotein concentrations and organization [76,81-83]. This leads to co-clustering of FADD and procaspase-8 into membrane rafts and thus activated formation of DISC. Remarkably Edelfosine is highly selective for leukemia cells and solid tumors compared with normal cells, where it targets only the plasma membrane rafts of leukemia cells and endoplasmic rafts of solid tumor cells [84].


Small Molecules Rewiring Lipid Metabolism in Cancer

Cancer cells display a highly distinct metabolic growth profile compared with non-transformed normal cells. The metabolic reprogramming of the enzymes of various pathways of cell growth forms the underlying basis of cancer. One of the most implicated pathways that are heavily tinkered with in cancer is lipid metabolism. Lipid metabolism is linked closely with the glycolytic pathway by virtue of it providing the required starting substrate–acetyl CoA–for Fatty Acid (FA) synthesis. Lipids play key roles in this network, as they are crucial for the formation of cell membranes and also act as signaling messengers. Due to the enormous up-regulated growth rate of cancer cells, relatively larger amounts of lipids are required to keep up with alarming rates of growth, proliferation, energy storage and production of signaling molecules [51,85]. Targeting lipid metabolism encompassing perturbing synthesis, oxidation and mobilization of lipids—is promising strategy in cancer treatment. One of the important steps in lipid metabolism is the formation of fatty acid, which uses acetyl CoA as a substrate. Acetyl CoA is either obtained from the glycolytic pathway via the conversion of pyruvate or by the breakdown of citrate into acetyl CoA and oxaloacetate by cytoplasmic ATP citrate lyase (ACLY). Acetyl CoA binds with malonyl CoA (formed via the carboxylation of acetyl CoA) to form palmitate, which is a starting product of FA synthesis via the enzyme Fatty Acid Synthase (FASN). Inhibitors against ACLY will lead to the reduced production of acetyl CoA and in turn reduce the levels of FAs that are formed. ACLY inhibition has been shown to cause growth suppression and induce apoptosis [86]. SB-204990 is shown to inhibit ACLY and therefore block the synthesis of FA and cholesterol. This causes a block in the cancer cell growth and the suppression of tumor, leading to cell death [87]. The next main step amenable to small molecule targeting is the formation of Palmitate by FASN. Palmitate is then converted by a set of enzymes to form an array of saturated and unsaturated FAs. FASN has been well documented with regard to its role played in cancer and is exploited extensively as anti-cancer target [88]. Targeting FASN has been demonstrated to lead to the de novo FA synthesis in cancer cells to reduce as most normal cells would prefer- the exogenous sources of FA. For example, Cerulenin, an antifungal agent, is one such inhibitor of FA synthesis, which reduces FA synthesis and rescues tumorous cells [89,90]. Another such drug is C75 that has been shown to cause the inhibition of FASN [91].


Small Molecules Targeting Lipid Re-Localization and Lipoprotein Sorting

Next to targeting the enzymes involved in lipid biosynthesis, targeting lipid oxidation and mobilization/localization are fruitful therapeutic avenues gaining recent interest. Carnitine Palmitoyltransferase 1 (CPT1) is an enzyme involved in the β -oxidation of FAs, where it facilitates the movement of FA-CoA from the cytosol to the mitochondria across the mitochondrial membrane. Etomoxir and Perhexiline are two small molecules shown to be effective against tumors and curb their proliferation via targeting FA oxidization mediated through CPT1 [92,93]. The FAs can once successfully translocated can either be diverted for storage or mobilized from stores as and when needed. The enzymes involved in these mechanisms have proven to be suitable targets for cancer therapies. Glycerol-3-Phosphate Acyl Transferases (GPATs) and its isoforms enable formation of Diacylglycerols (DAG) and Triacylglycerols (TAG), which are then directed towards storage, while enzymes like Monoacylglycerol Lipase (MAGL) mobilize FAs from their reservoirs. CT-30501 inhibits GPATs while JZL184 inhibits MAGL. These small molecules help in suppression of tumor growth and induce apoptosis respectively [94]. The above are just a few examples of the use of small molecules to target lipid metabolism and associated processes in cancer cells and form a firm foundation of lipid-targeted cancer therapies. One of the salient features of lipid membranes is the asymmetric distribution of lipids, such lipids PS and PE. They are largely present in the leaflet facing towards the cytosol, however upon exposure to the cell surface they act as markers for signaling pathways. Therefore, this feature of the membrane’s asymmetric distribution of composing lipids makes it an important target to fight against much human pathology, and certain lipids are extensively used as biomarkers against cancer attributed to the fact of cancer cells expressing high levels of PE and PS exposed on its outer leaflet. PE acts as a structural component of cell wall as well as is implicated in many cellular processes like cell division and cell death, thus a highly sought-after anti cancer target [2]. Cyclotides are cyclic peptides that have a high affinity to target and bind to PE head groups modulating their localization and disturbing downstream cellular functions involving PE. Along with cyclotides, there are two lantibiotic peptides– Cinnamycin and Duramycin–that are also PE specific and are produced by gram-positive bacteria. The binding of both these types of peptides have a membrane disruption effect that causes cell death [95,96].
Lipid apart from being intimately involved in cellular functions and cellular signaling as isolated modules, they add another level of complexity by their covalent attachment to proteins—posttranslational protein lipidation—that forms the heart of membraneassociated signaling in cells, e.g. small GTPases, such as Ras, Raf, and ARFs etc. A classic example of addressing oncogenic signaling involving lipidated proteins is via targeting the protein lipidation leading to improper membrane-raft localization of these proteins causing non-functional signaling platforms and hence subdued oncogenic signaling. This aspect is greatly exemplified by the class of lipidated protein-Ras. The lipid moieties attached to the protein consist of a palmitoyl group and 1-2 farnesyl lipid anchors. As mentioned above, Ras was the first oncogene to be discovered and is involved in many human cancers; however small-molecule targeting of Ras still remains an unmet task in cancer therapy. One of the attempted ways by which membrane-associated Ras oncogenic signaling has been targeted is via inhibiting the activity of farnesyl transferase to block farnesylation of Ras and hence reduce its membrane raft association and concomitant signaling in cancer cells [97-99]. More than two decades were invested to exploit this approach as a practical anticancer therapy but has met with many deadlocks mainly ascribed to the non-selective nature of farnesyltransferase inhibitors [100]. Amidst such failed attempts, recently Waldmann and co-workers have demonstrated an exciting alternative to target Ras-associated cancer by mis-localizing Ras lipoprotein not channelized via blocking the lipid attachment but by an innovative chemical biology approach [101]. Lipidated Ras is trafficked through a prenyl-binding protein, PDEδ in cells that sustains the spatial orientation of the Ras super family of proteins [102].
Recently high specificity of PDEδ towards K-Ras trafficking to reach plasma membrane rafts to initiate signaling was demonstrated, and the same was exploited by designing small molecules such as Deltarasin and related analogs to block the binding pocket of PDEδ leading to K-Ras mislocalization and down-regulated cancer signaling leading to reduces cell proliferation and finally cancer cell death [101,103-104]. This study provides a proof-of-concept platform and opens various channels aimed at targeting lipids-mediated cellular functions in unprecedented ways. Although a lot of work has to be yet done in identifying cancer specific small molecule against cancer cells, the effects of presently available small molecule on the membrane specific organization and signaling are proven as an effective.


Conclusions and Future Directions

The quest for targeting cancer using varied chemical and genetic approaches still is faced with enormous hurdles and generates a unmet need to develop therapeutic approaches inspired by careful inspection of modulated cancer cell attributes. One of the aspects gaining considerable attention recently has been the altered lipid repertoire of cancer cells leading to modulated membrane-dependent cellular processes including membrane organization and cellular signaling, strongly contributing to tumor growth and metastasis and understanding the underlying mechanism behind the same to elucidate potentially novel targets and pathways against cancer. In this review we focused on some of the most promising lipid associated candidates and processes for anti cancer targeting by small molecules. Ranging from targeting of lipid enzymes involved in the lipid metabolic pathway to the proteins and lipids that help in lipid organization, oncogenic lipoprotein sorting and signaling membrane micro domains-rafts have proven to be highly crucial to not only contemplate their therapeutic aspect but also address and unveil specific mechanisms of lipid deregulation in cancer. Further chemical biology investigations on the regulation of membrane lipid-dependent signaling pathways in cancer cell may provide novel targets for therapy and elucidating the role of distinct lipid signaling molecules will offer innovative therapeutic opportunities for development of anti-cancer drugs.


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