Appl Microbiol Biotechnol (2013) 97:8849–8857 DOI 10.1007/s00253-013-5227-9

MINI-REVIEW

TRAIL and microRNAs in the treatment of prostate cancer: therapeutic potential and role of nanotechnology Ammad Ahmad Farooqi & Giuseppe De Rosa

Received: 17 May 2013 / Revised: 30 August 2013 / Accepted: 2 September 2013 / Published online: 15 September 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Disruption of spatiotemporal behavior of intracellular signaling cascades including tumor necrosis factor alpharelated apoptosis-inducing ligand (TRAIL)-mediated signaling in prostate cancer has gained tremendous attention in the past few years. There is an increasing effort in translating the emerging information about TRAIL-mediated signaling obtained through experimental and preclinical data to clinic. Fascinatingly, novel targeting approaches are being developed to enhance the tissue- or subcellular-specific delivery of drugs with considerable focus on prostate cancer. These applications have the potential to revolutionize prostate cancer therapeutic strategies and include the accumulation of drugs in target tissue as well as the selection of internalizing ligands for enhanced receptor-mediated uptake of drugs. In this mini-review, we outline outstanding developments in therapeutic strategies based on the regulation and/or targeting of TRAIL pathway for the treatment of prostate cancer. Moreover, microRNAs (miRNAs), with potential transcriptional and posttranscriptional regulation of gene expression, will be presented for their potential in prostate cancer treatment. Emphasis has been given to the use of delivery approaches, especially based on nanotechnology. Considerably, enhanced information regarding miRNA regulation of TRAIL-mediated signaling in prostate cancer cells may provide potential biomarkers for the characterization of patients as responders and nonresponders of TRAIL-based therapy and could provide rationalized basis for combination therapies with TRAIL death receptor-targeting drugs.

A. A. Farooqi (*) Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College, 35 Km Ferozepur Road, Lahore, Pakistan e-mail: [email protected] G. De Rosa Department of Pharmacy, Università Degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy

Keywords TRAIL . miRNA . Nanotechnology . Prostate cancer . Signaling cascades

Introduction Prostate cancer is a multifaceted disease, and heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity. Genomic rearrangements, overexpression of oncogenes, loss of tumor suppressor genes, and pro-survival signaling pathways integrate and generate a cumulative effect. Misrepresentation of signaling cascades is an important aspect that plays a predominant role in prostate cancer progression. The genetic basis of prostate cancer is a cornerstone of modern cancer research that began to unravel over decades ago. Because of high impact research, this concept has undergone substantial broadening after gaining insights into the mechanisms underlying chromosome imbalances, increased mutation rates, and other forms of genetic instabilities, and many of which are relevant to the development of prostate cancer. In the upcoming section, we focus on tumor necrosis factor alpharelated apoptosis-inducing ligand (TRAIL)-mediated signaling and oncosuppressor microRNAs (miRNAs) which have gained appreciation and shown promise in inducing apoptosis in cancer cells with minimal off-target effects. Moreover, emphasis has been given to the potential of nanotechnology to deliver miRNAs or drugs related to TRAIL-mediated signaling in prostate cancer cells.

TRAIL-mediated signaling: a targeted killing of cancer cells There is a continuous addition of regulators of apoptosis that has increased our understanding on the positive and negative regulation of apoptosis. Thus, one of the major breakthroughs in apoptosis biology is the identification of TNF superfamily consisting on proteins involved in proliferation, differentiation,

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and apoptosis. Various review articles address modes and mechanisms which impair TRAIL-mediated signaling cascade. Reasonable knowledge of the relationship between different cell death pathways as well as between cell death and pro-survival pathways in cancer is essential for identification of prospective convergence points between signaling cascades (Farooqi et al. 2012a, b). TRAIL belongs to a small subset of pro-apoptotic protein ligands in the TNF superfamily which also includes TNF and CD95L (FasL/APO-1L). The field of TRAIL-mediated signaling in cancer cells was explored overwhelmingly after the first experimental report that revealed TRAIL-mediated apoptosis in cancer cells leaving normal cells intact (Pan et al. 1997). There was a rapidly mounting interest of researchers in studying molecular characteristics of TRAIL-mediated signaling in prostate cancer cells, and experimental data shed light on TRAIL-mediated apoptosis in PC-3 and DU145 cells (Yu et al. 2000). Parallel in-depth studies related to death receptors in cancer cells provided wealth of information that, in death, receptors were found to be underexpressed resulting in a loss of TRAIL-induced apoptosis in cancer cells. Scientists started searching for various mechanisms which can restore TRAILmediated apoptosis in resistant cancer cells. Surprisingly, it was suggested that pretreatment of prostate cancer cells with chemotherapeutic drug paclitaxel helped in the restoration of apoptotic pathway. It was observed that the sensitivity of resistant cancer cells towards TRAIL was regained because of increase in the expression of death receptors after treatment with paclitaxel (Nimmanapalli et al. 2001). TRAIL-induced cellular signaling occurs through death receptors 4 and 5. The attachment of ligand to its specific receptor results in trimerization of the receptor and recruitment of Fasassociated death domain (FADD) containing protein. Attachment of adaptor protein to cytoplasmic domain of death receptor results in subsequent recruitment of the initiator caspase 8 and/or caspase 10. Procaspase-8 upon activation acts on its downstream effector caspase 3. Caspase 3 is a downstream effector to either extrinsic pathway consisting of caspase 8mediated activation or intrinsic pathway that is activated upon release of cytochrome c. Released cytochrome c forms a complex with procaspase-9 to form active caspase 9. Intrinsic pathway initiates by translocation of Bid (pro-apoptotic protein) to a mitochondrion. This consequently results in aggregation of Bax/Bak which provides passage for cytochrome c and Smac/DIABLO by formation of mitochondrial pore (Schneider et al. 1997; Sheridan et al. 1997; Walczak et al. 1997; Pan et al. 1997). The pathway is represented in Fig. 1.

Antitumor activity of TRAIL using nanoparticles It is getting increasingly clear that nanoscale drug delivery systems are rapidly emerging technologies for the rational

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delivery of chemotherapeutic drugs in the treatment of cancer. Substantial fraction of information has revealed that compared with free antitumor drugs, drug-loaded nanovectors can promote enhanced accumulation in tumor tissues and betterquality therapeutic activity. The encapsulation of drugs into the colloidal particles can be used to change drug biodistribution. In the case of solid tumors, the enhanced permeability of the capillaries and the lack of functional lymphatic lead to an increased nanoparticle accumulation into target tissue. This effect, also known as enhanced permeability and retention (EPR) effect has been successfully used to enhance drug delivery in solid tumor, with reduced drug release into the healthy tissues (Seymour 1992; Maeda et al. 2000). The development of stealth nanoparticles (i.e., polyethylene glycol (PEG)ylated nanocarriers), characterized by reduced capture by the cells of the reticuloendothelial system and prolonged circulation time in the bloodstream, certainly represents a milestone for delivery of chemotherapeutics (Gabizon and Martin 1997; Cattel et al. 2004; Moghimi and Szebeni 2003). Nanoparticle functionalizing with targeting moieties can promote specific receptor-mediated endocytosis, limiting nonspecific uptake into the normal cells (Basile et al. 2012; Holgado et al. 2012). Different nanotechnology-based formulations have been proposed to efficiently deliver TRAIL in different animal models of cancer. Recombinant TRAIL was complexed with different polymers, achieving nanocomplexes with improved TRAIL half-life and enhanced antitumor activity (Lim et al. 2011; Na et al. 2008). Recently, TRAIL has been conjugated to magnetic ferric oxide nanoparticles (NPs), leading to an increased apoptotic activity against different human glioma cells and GSCs, as compared with free recombinant TRAIL (Perlstein et al. 2013). Moreover, in U251 glioma cell-derived xenografts, a significant increase in glioma cell apoptosis, a decrease in tumor volume, and increased animal survival were reported. Nanocarriers have also been used to co-deliver TRAIL and other classic chemotherapeutics, in order to overcome resistance to TRAIL-induced apoptosis. Thus, actinomycin D or doxorubicin were co-encapsulated with TRAIL in long-circulating liposomes, showing a synergistic cytotoxic effect against non-small cell lung cancer (NSLC) (Guo et al. 2012) and glioblastoma multiforme (GBM) cancer cells (Gu et al. 2013). With the same systems, enhanced inhibition of tumor growth in NSLC or GBM animal model, without significant general toxicity, was reported. Efficient co-delivery of recombinant TRAIL and chemotherapeutic drugs (i.e., doxorubicin and paclitaxel) with micellar nanoparticles selfassembled from a biodegradable cationic copolymer P(MDS-co -CES) was demonstrated (Lee et al. 2011a, b). Interestingly, cytotoxicity of the nanocomplexes was significantly lower in noncancerous cells than in cancerous cells. Alternatively, nanovectors have been proposed to delivery TRAIL-encoding plasmid. Cationic liposomes (ANG-CLP)

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Fig. 1 TRAIL-mediated signaling. Additionally, extrinsic and intrinsic pathways are represented. Extrinsic pathway is initiated through death receptors in which caspase 8 activates caspase 3. Intrinsic pathway is functionalized through mitochondria. Truncated bid moves into mitochondria that triggers release of cytochrome c, Smac/DIABLO, from

mitochondria. Interestingly, miRNAs have been reported to regulate TRAIL-mediated signaling via regulation of pro-apoptotic and anti-apoptotic proteins. Anti-apoptotic proteins including Bcl-2 and Bcl-xl are negatively regulated by miR-205 and miR-574-3p. Pro-apoptotic proteins including p53, Puma, and Noxa are negatively regulated by miR-125b

were used to efficiently co-deliver TRAIL-encoding gene and paclitaxel (PTX) to glioma cells (Sun et al. 2012). In accordance with similar approach, another study proposed cationic liposomes to co-transfected colon cancer cells with tyrosine kinase receptor 3 ligand and TRAIL-encoding plasmids (Sun et al. 2012). It has recently been documented that artificial lipid vesicles coated with bioactive Apo2L/TRAIL, resembling to natural exosomes, have a noteworthy apoptosisinducing ability in cancer cells (De Miguel et al. 2013).

In a different approach, Salmonella typhimurium strains have recently been engineered to secrete TRAIL, and experimental evidence indicates that Salmonella-mediated tumor-targeted therapy with TRAIL effectively reduces tumor growth (Chen et al. 2012). In another study, TRAIL fused with an antibacterial peptide was expressed in Escherichia coli; the purified product was effective against K562 leukemia cells and HepG2 liver carcinoma cells (Liu et al. 2013).

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TRAIL has also been used to design targeted nanovectors. According with this approach, surface modifications of human serum albumin (HSA) NPs with thiolated TRAIL or transferrin and encapsulating doxorubicin have demonstrated enhanced cytotoxic and apoptotic activities, compared to unmodified HAS-NPs, in all cancer cells (Bae et al. 2012). More prominently, doxorubicin and therapeutic gene pTRAIL-loaded host–guest co-delivery system has shown potential in restricting tumor growth (Fan et al. 2012). Likewise, chemotherapeutic drug-loaded polylactic acid (PLA) NPs covalently conjugated to a TRAIL receptor 2 (DR5) monoclonal antibody (mAb) act as potent anticancer agents (Ding et al. 2011). Finally, an enhanced activity of a micellebased formulation encapsulating a chemotherapeutic was achieved on TRAIL-resistant cancer cells by combining TRAIL and a cancer-targeting anti-nucleosomal mAb2C5 antibody on the micelle surface (Skidan et al. 2009). Nanotechnology has been largely investigated to target prostate cancer (Sanna and Sechi 2012). For example, our group recently demonstrated the potential of different delivery systems to deliver drugs in an experimental model of prostate cancer (Marra et al. 2011, 2012; Salzano et al. 2011). Although, at our knowledge, nanovectors for delivery of TRAIL have been rarely used in prostate cancer, this approach is now on the flying carpets and will be certainly explored in the next time.

miRNA control of apoptosis in prostate cancer cells Emergence of miRNA has doubtlessly deepened our current understanding on the intricacy of mammalian genome with particular emphasis on transcriptional and posttranscriptional regulation of gene expression. These are further characterized into subcategories including tumor suppressors, oncomirs and metastamirs. In the next section, we briefly discuss miRNA subsets which are misrepresented in prostate cancer cells and contribute to resistance against apoptosis. In particular, there are wide ranging miRNA subsets which regulate proapoptotic and apoptotic genes, thus controlling survival of prostate cancer cells. Therapeutic potential of miRNAs to repress oncogenes and restoration of apoptosis in cancer cells are being explored. However, there are major knowledge gaps related to the therapeutic use of nucleic acid, namely, short half-life in the blood and poor uptake into the cells (De Rosa and La Rotonda 2009), which need to be bridged for an effective translation of this technology into the clinic. Thus, a therapy based on nucleic acids, e.g., miRNAs, requires the development of a specific delivery strategy, i.e., viral and non-viral vectors. Viral vectors allow achieving high levels of transfection with different types of nucleic acids, among them miRNAs. For example, expression of miR-338-3p in colorectal carcinoma cell line (SW-620)

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transduced with the lentivirus vector displayed a decrease in cancer growth (Sun et al. 2013). However, if compared with virus, non-viral vectors are more safe and cheap and can be proposed to develop miRNA-based therapies. Nanovectors can be designed not only to increase the miRNA uptake into the cells but also to target tumors and, more specifically, cancer cells. A huge number of papers demonstrated the usefulness of nanovectors to deliver oligonucleotide in preclinical model of cancer, and some nanotechnology-based products are, at the moment, in clinical trials. In all cases, a cationic molecule, namely, a cationic lipid or polymer, is mandatory to allow nanovector encapsulation/complexation with the oligonucleotide. The presence of PEG on the nanovector surface can confer the stealth properties as well as stability in serum. Moreover, the presence to ligands on the surface can allow to actively target cancer cells and, in some cases, to increase the nanovector uptake into the cytoplasm (De Rosa et al. 2010). A number of ligands have been proposed as targeting moieties for cancer cells. Lipid-based nanovectors, e.g., cationic liposomes, are certainly the most investigated non-viral delivery systems for nucleic acids (De Rosa et al. 2010). These are characterized by a cationic lipid able to complex the nucleic acid and to mediate the uptake into the cells. A more recent development of these systems are the stable nucleic acid lipid particles (SNALPs) that are characterized by a ionizable lipid that assure high nucleic acid entrapment in the protoned form and higher stability in serum upon charge neutralization on the particle surface (Semple et al. 2001). The efficacy of this delivery system has been shown in mammalian primates to deliver small interfering RNA (siRNA) (Zimmermann et al. 2006), and clinical trials are ongoing. The possibility to use this system to deliver miRNAs has been recently demonstrated (de Antonellis et al. 2011) and could be certainly applied to prostate cancer. Insights from biodegradable polymers research are catalyzing new lines of study to form polymeric NPs to encapsulate a variety of therapeutic compounds. FDA-approved polymers or newly synthesized polymer and copolymers have been proposed for the delivery of nucleic acids (Fattal and De Rosa 2008). Nanoparticles based on different biodegradable neutral polymers, e.g., poly(D ,L -lactic-co -glycolic acid) (PLGA), have been proposed not only to target tumor tissues but also to prolong the delivery of nucleic acids. Use of agents with remarkable buffer capacity has also emerged as a worthwhile methodology that primarily depends on cationic groups contained in polymers such as polyethylenimine (PEI) or in polypeptides. It has been convincingly revealed that polymers and cationic polypeptides mediated flow of protons into endosomes generating an osmotic pressure that resulted in rupture of the endosome. Protamine is an arginine-rich polypeptide, and there is a rapidly accumulating evidence obtained experimentally that the condensation of nucleic acids with

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protamine is also an efficient strategy. Recently, PEI has been successfully used to transfect miR-150 in reconstituting human leukemia cells (K-562 and KU812) (Avci et al. 2013). As follows, different miRNAs that could be considered of interest for prostate cancer treatment are reported, together with example of delivery strategy used.

Oncogenic miRNAs Among the oncogenic miRNAs, the mi181b has been found to be overexpressed in prostate cancer. Recently, it has been shown that the inhibition of miR-181b induced apoptosis in prostate cancer cells (He et al. 2012). Compelling data suggests that miR-21 negatively regulates matrix metalloproteinase inhibitor, RECK, thus promoting invasive behavior of prostate cancer cells (Reis et al. 2012). Detailed mechanistic insights provide reasonable proof that miR-21 promotes invasive potential of prostate cancer cells via regulation of wideranging tumor suppressors. Myristoylated alanine-rich protein kinase c substrate (MARCKS) is also a target of miR-21 (Li et al. 2009). Additionally, there are some other genes which are tumor suppressors and negatively controlled by miR-21 including ANP32A and SMARCA4 (Schramedei et al. 2011). miR-21 is overrepresented in prostate cancer cells, and targeted inhibition of miR-21 restored apoptotic pathway in prostate cancer cells (Li et al. 2009). It is relevant to mention that transient transfection of miR-21 in prostate cancer cells induced resistance against docetaxel (Shi et al. 2010). Mounting evidence suggests that miR-106b∼25 cluster is located within intron 13 of the minichromosome maintenance protein 7 (MCM7) gene. Therefore co-expression of MCM7 and miR-106b-25 mediated prostatic intraepithelial neoplasia in transgenic mice. Moreover, PTEN is a phosphatase and is negatively regulated by miR-106b-25 (Poliseno et al. 2010). It is interesting to note that miR-106b-25 posttranscriptionally controls the expression of ZBTB4 (zinc finger and BTB domaincontaining 4). ZBTB4 is a tumor suppressor that is reported to be involved in repressing Sp transcription factor-specific target genes. It inhibits the expression of specificity protein (SP)targeted genes by competitively binding to SP-specific promoter regions (Kim et al. 2012a, b). miR-106b-25 miRNA cluster negatively regulates caspase 7 (Hudson et al. 2013). There are contradictory reports related to miR-125b regulation by androgen signaling. There is a direct piece of evidence that suggests that AR represses miR-125b to derepress the expression of different mRNA transcripts (Sun et al. 2013). Contrary to this, there is a report that indicates that androgen signaling stimulates the expression of miR-125b, and it has been shown that the targeted inhibition of miR-125b resulted in suppression of androgen-independent growth (Shi et al. 2007). miR-125b negatively regulates different pro-apoptotic genes including p53, Puma, and Bak1 (Shi et al. 2011).

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Tumor suppressors miR-205 is a tumor suppressor and is underexpressed in prostate cancer cells. Transient transfection of miR-205 in prostate cancer cells induced apoptosis. It is astonishing to note that miR-205 is directly involved in stimulating the expression of tumor suppressor genes IL24 and IL32 (Majid et al. 2010). It is also involved in the negative regulation of Bcl-2. Prostate cancer cells reconstituted with miR-205 upon treatment with cisplatin and doxorubicin displayed a considerable increase in apoptosis (Verdoodt et al. 2013). miR-5743p controls Bcl-xL and notably induces apoptosis in prostate cancer cells. miR-574-3p is underexpressed in prostate cancer cells, and it has been shown that cells treated with genistein demonstrated an increase in the expression of miR-574-3p (Chiyomaru et al. 2013). Polycomb group gene Bmi-1 is overexpressed in prostate cancer stem cells; however, it has previously been shown that cells treated with NVP-LDE-225 (erismodegib) remarkably displayed a decrease in the expression of Bmi-1. It is worth mentioning that erismodegib is reported to be involved in the negative regulation of Bmi-1 by upregulating the expression of miR-128. Interference strategies using antagomirs against miR-128 provided evidence that erismodegib-directed apoptosis was significantly impaired (Nanta et al. 2013). We still have incomplete information of miRNA subsets which positively and negatively regulate TRAIL-mediated signaling in prostate cancer cells. However, certain clues have emerged that indicate that the enforced expression of miR-133b in prostate cancer cells restored TRAIL-mediated apoptosis in prostate cancer cells (Patron et al. 2012). miR-130a, miR-203, and miR-205 have been studied in prostate cancer cells, and it is relevant to mention that the reconstitution of LNCaP cells with these miRNAs resulted in induction of apoptosis (Boll et al. 2012). It is appropriate to mention that miRNA subsets underexpressed in prostate cancer cells can be used to regulate the proficiency of cancer-specific adenoviral vector that expressed TRAIL based on miRNA response elements (MREs) of miRNAs whose levels were reduced in prostate cancer. Similar approaches have been tested in bladder cancer and glioma using adenoviral vector expressing TRAIL and introducing MREs of miRNA subsets downregulated in respective cancer cells (Zhao et al. 2013; Bo et al. 2013). The bifunctional peptides can target cell surface receptors expressed abundantly on tumor cells and carry cargo molecules inside the cells efficiently. Therefore, cationic microRNAdelivering nanovectors with bifunctional peptides have shown tremendous efficiency in PANC-1 cell lines (Hu et al. 2013). Accumulating evidence provides considerable advances in drug delivery systems, and it has been experimentally shown using virus-like particles (VLPs) as biological constructs that are enveloped with certain proteins derived from the outer coat of a virus. Precursor of miR-146a (pre-miR146a) was inserted

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Table 1 Receptors overexpressed on prostate cancer cell surface and can be targeted for effective uptake of the drug Receptors overexpressed on prostate cancer cell surface

Reference

α(v)β(3) integrin Prostate-specific membrane antigen (PSMA) Laminin receptor FGFR FcRs of human DCs Urokinase plasminogen activator receptor (uPAR)

Graf et al. (2012) Zhao et al. (2012) Shukla et al. (2012) Szlachcic et al. (2012) Cruz et al. (2011) Abdalla et al. (2011)

into a prokaryotic expression vector and co-expressed with the capsid protein of bacteriophage. These particles conjugated to a HIV-1 Tat47-57 cell-penetrating peptide efficiently delivered miR-146a systematically in mice (Pan et al. 2012). Delivery of tumor suppressor miRNAs into cancer cells using cysteaminefunctionalized gold nanoparticles (AuNPs) is also an attractive option and needs to be explored in prostate cancer cells (Ghosh et al. 2013). Disialoganglioside (GD2) is a glycolipid highly expressed on the cell surface of neuroblastoma and several other cancers, and accordingly, targeted delivery of miR-34a using anti-disialoganglioside GD2-coated nanoparticles was effective in decreasing tumor load in murine orthotopic xenograft disease model (Tivnan et al. 2012). It has been shown convincingly that hTERT promoter can direct target gene expression preferentially in cancer cells. In line with this approach, T promoter is integrated into VP16Gal4-WPRE integrated systemic amplifier (VISA) system to upregulate transgene expression. miR-34a expression plasmid (T-VISA-miR-34a) using the T-VISA system is an important application of this system and has been reported to effectively inhibit tumor growth (Li et al. 2012).

Oncomirs Another approach consists on the development of selfassembling nanoscale device based on polylysine which main chain acted as hydrophobic core, and the cationic side chain of lysine served as a hydrophilic surface corona. Cationic side chain of lysine interacts with negatively charged RNA molecules. PLL-anti-mir particles slowly release a small amount of antagomirs to inhibit the mature target miRNA that is overexpressed in cancer cells (Jin et al. 2012). This approach has tremendous potential that needs validation in prostate cancer subtypes overexpressing oncomirs. Finally, systemic delivery of antisense peptide nucleic acids encapsulated in polymer nanoparticles has been proposed as an

alternative strategy to inhibit overexpressed miRNAs in prostate cancer cells (Babar et al. 2012). It is foreseeable that in the next future, a number of papers will report results of a more specific delivery of miRNAs by conjugating ligands for which receptors are overexpressed on the membrane of prostate cancer cells. Table 1 reports some examples of receptors that are overexpressed in prostate cancer and that can be potential ligands for targeting of prostate cancer cells.

Conclusion The rapidly increasing information regarding the mechanisms that regulate cell death pathways in a positive or negative manner has offered new horizons to cancer biologists to target these pathways as an anticancer strategy. There is considerable progress in identifying the protein network which regulates TRAIL-mediated signaling in prostate cancer. Furthermore, in wide-ranging synthetic compounds, herbal extracts are tested in androgen-sensitive and androgen-insensitive prostate cancer cell lines and animal models to restore TRAIL-mediated apoptosis. However, how miRNA controls TRAIL-mediated signaling is still incompletely understood in prostate cancer. Emerging data highlights cell-type-specific miRNA regulation of TRAIL-mediated signaling; however, a deeper understanding on subsets of tumor suppressor and oncogenic miRNAs is necessary. Moreover, how miRNA posttranscriptionally regulates TRAIL and death receptor in prostate cancer cells, which oncogenic miRNA subsets are underexpressed that consequently results in overexpression of anti-apoptotic proteins, needs detailed research. In addition, it will also be helpful in identifying rational strategies for drug discovery that can work effectively with nanoparticle encapsulating TRAIL to stimulate the expression of death receptors, thus maximizing the usefulness of TRAIL in integrated preclinical and clinical trials. Moreover, combinatorial approach needs to be tested in preclinical trials. There is limited information regarding co-treatment with TRAIL and tumor suppressor miRNAs. In accordance with similar approach, TRAIL can be combined with antagomirs and can be tested for its efficacy. Also in this case, the use of non-viral nanovectors can be a useful strategy to overcome biopharmaceutical issues. Despite the fact that the recapitulation of cell death pathways is challenging, recent studies exploring the cell death machinery have identified various approaches, especially a multipronged approach to circumvent TRAIL-mediated resistance. Acknowledgments The author would like to acknowledge and appreciate the efforts of Miss Maira Mariam for English language editing and better presentation of the review.

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