see url Journal List Acta Naturae v. Acta Naturae. Ukrainskaya , A. Stepanov , I. Glagoleva , V. Knorre , A. Belogurov , and A. Ukrainskaya M. Stepanov M. Knorre M. Belogurov M. Gabibov M.
Author information Article notes Copyright and License information Disclaimer. Stepanov: moc. Received Jun 2. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC.
Abstract This article offers a detailed review of the current approaches to anticancer therapy that target the death receptors of malignant cells. Open in a separate window. References 1. Deyev S. Wong R. Cancer Res. Parameswaran N. Gene Expr. Strater J. Pan G. Chinnaiyan A. Reed J. Wang T. Breast Cancer Res. Natoni A. MacFarlane M. Cancer Research. Ren Y. Chiron D. Clancy L. Sfikakis P. Ozoren N. Cancer Biol. Marconi M. Cell Death Dis.
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Jun 2, This article offers a detailed review of the current approaches to anticancer therapy that target the death receptors of malignant cells. Here, we. Oct 6, Introduction. Death receptor signalling. TNF-R1 signalling. CD95 signalling. TRAIL-R signalling. Targeting death receptors in cancer therapy.
Pitti R. Wiley S. On the other hand, triggering tumor cell apoptosis, in general, is the foundation of many cancer therapies. In the case of CSCs, it was suggested that the induction of apoptosis in the CSC fraction of tumor cells by specifically upregulating death receptors or death receptor ligands such as TRAIL is a potential strategy to bypass the refractory response of CSCs to conventional therapies [ 38 ].
Preclinical studies have demonstrated the potential of TRAIL to selectively induce apoptosis of tumor cells, because normal cells possess highly expressed decoy receptors that protect them from cell death [ 20 , 39 ], which has driven the development of TRAIL-based cancer therapies [ 38 , 40 ]. Unfortunately, a considerable range of cancer cells, especially in some highly malignant tumors, are resistant to TRAIL-induced apoptosis [ 41 ]. PEITC treatment in hCSCs reduced proliferation and sphere formation and expressed higher levels of cPARP, indicating elevated levels of apoptosis, which is possibly through caspase activation by isothiocyanate in treated cancer cells as reported previously [ 42 ].
At similar micromolar concentrations, the effects of PEITC on hCSC proliferation were comparable to salinomycin, which was shown to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers [ 37 ]. It is worth mentioning here that salinomycin had considerable cytotoxicity in healthy mammals [ 37 ].
PEITC has been well documented for safety to normal mammals. It is interesting to investigate if PEITC is cytotoxic to normal stem cells, which has not been reported. This better anti-proliferative effect may be due to the high level of chemoresistance of CSCs to paclitaxel, the overcoming of which by specific targeting of CSCs is hailed as critical. TRAIL is known to trigger apoptosis through binding to DR4 or DR5, which contain cytoplasmic death domains responsible for recruiting adaptor molecules involved in caspase activation [ 21 ].
While the biological activity of PEITC in inducing apoptosis of cancer cells may involve death receptor signaling, other mechanisms have also been suggested [ 12 , 13 ]. Finally, to investigate the antagonistic effects of PEITC on hCSC tumorigenicity in vivo , we carried out xenotransplantation in immune-compromised mice. Mice receiving untreated hCSCs produced the highest numbers of tumors and also showed greater invasiveness, as confirmed by the presence of lung metastases. However, given the short 3-week duration of the experiment, metastasis was found in only one of the four animals in the hCSC group but in no other animal in the remaining groups.
It should be noted here that the sphere culture approach to isolation of hCSCs that we used in the study followed by cell-surface marker-based characterization helps to identify CSC-enriched subpopulations but did not enable unambiguous isolation of all of the CSCs. Collectively, our data strongly justify future clinical trials of PEITC, individually or in combination with recombinant TRAIL therapy, for improved treatment outcomes in cancer patients. Support Care Cancer.
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Another study demonstrated that RNAi targeting of XIAP increased breast and pancreatic cancer cell susceptibility to functionally diverse chemotherapeutic agents, including TRAIL and taxanes and therefore increasing the effectiveness of chemotherapeutic agents[ 83 ]. Furthermore, in vivo studies also demonstrated that inhibition of XIAP by RNAi radiosensitized lung cancer cells by up-regulating apoptotic signaling and down-regulating cell survival[ 84 ].
Clinical trials using anti-sense oligonucleotide AEG is proving to be successful. The first-in-human study with AEG in patients with advanced refractory cancers demonstrated that the compound was well tolerated and showed some anti-tumor activity[ 83 ]. However, AEG was less effective in Phase I clinical trials with pancreatic cancer patients[ 85 , 86 ]. Therefore, RNAi therapy shows significant promise in treating apoptosis-resistant cancers.
Mol Cancer Ther 9 12 — Death receptor 5 internalization is required for lysosomal permeabilization by TRAIL in malignant liver cell lines. The fluorescence was measured using an Epics Elite flow cytometer Beckman Coulter. Genomic translocations, such as t 11;18 q21;q21 , results in the fusion of the BIR domains of cIAP2 with paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 MALT1 and occurs frequently in mucosa-associated lymphoid tissues[ 52 - 54 ]. Eventually, the autophagsome fuses with the lysosome and degrades its interiors to provide cells the nutrients such as amino acids or fatty acids necessary for cell metabolism[ ]. Ann Oncol 19 6 —7. Similarly, in normal fibroblasts, the ability of E1A to promote apoptosis depends on its ability to inactivate the retinoblastoma tumor suppressor, and cannot be separated from its transforming functions
While AEG demonstrates promise in treating primary refractive disease, it is important to identify the patients that express high levels of IAPs in order to gain the most therapeutic benefit. Again, this demonstrates the need for molecular marker screening in order to develop personalized therapies. Both the anti-apoptotic and pro-apoptotic functions of BCL-2 family members are regulated through their BH domains [ 91 , 92 ].
BCL-2 proteins are typically found at the outer mitochondrial membrane OMM , however, they can also be localized to the endoplasmic reticulum ER and in the cytosol[ 95 ]. Death signals induced by DNA damage, growth factor deprivation, or chemotherapies induce apoptosis via the mitochondrial pathway Figure 1 by transcriptional or post-translational activation of BH3-only proteins[ 96 - 98 ]. After activation, the pro-apoptotic BH3-only proteins prompt a conformational change of monomeric BAX and BAK resulting in homo-oligomerization and activation[ 99 - ].
Another model describes an indirect mechanism. It has been shown that BCL-2 undergoes a conformational change to bind to and inhibit oligomerization of mitochondrial membrane bound Bax. However, if BAX is in excess, apoptosis resumes due to the availability of free BAX able to activate the apoptotic pathway [ ].
The activation models, as described in the previous paragraphs, are simplified examples of the complex interactions required to carry out the intrinsic apoptosis pathway. Dysregulation of intrinsic apoptosis pathways, due to altered ratios of antiapoptotic members to proapoptotic members, leads to apoptotic blocks. Identifying the proteins involved in these blocks is essential for designing more effective rational therapies. It was demonstrated that BH3-only proteins show distinct binding preferences to anti-apoptotic BCL-2 family members[ , ].
Identifying differential BH3-only protein binding affinities for anti-apoptotic BCL-2 protein family members has led to the development of specific small molecule inhibitors of anti-apoptotic BCL-2 proteins which are designed to overcome apoptosis resistance in cancer cells and induce cell death. The dysregulation of BCL-2 family members, such as overexpression of anti-apoptotic genes or silencing of pro-apoptotic genes, is a key determinant for apoptosis-resistance during tumorigenesis and chemotherapy.
BCL-2 was initially discovered to be overexpressed in human B-cell lymphomas and is located near chromosomal translocation break points frequently found in B-cell lymphomas[ ]. Additional studies have demonstrated that BCL-2 protein levels in cancers are enhanced due to promoter hypomethylation, loss of inhibitory microRNA expression, and gene amplifications, signifying that up-regulation of BCL-2 expression is often found in a variety of cancers[ , ].
Expression of anti-apoptotic BCL-2 family members has a significant effect on chemoresistance and prognosis[ , ]. Alternatively, the pro-apoptotic BCL-2 family members can be down-regulated resulting in suppressed apoptosis. Spontaneous deletions or mutations of BAX have been observed in colorectal tumors, which results in significant reduction of apoptosis in response to anticancer agents[ , ].
Dysregulation of BCL-2 family of proteins also occurs in cancer cells due to a loss of p53 tumor suppressor expression or function. Interestingly, p53 has also been shown to inhibit anti-apoptotic BCL-2 family members as well. Inhibiting apoptosis via passociated regulation of the BCL-2 family displays another level of complexity in inducing cell death of cancer cells.
Due to the dysregulation and importance of BCL-2 family members for inhibiting apoptosis in cancer cells, attempts aimed at developing novel drugs that can inhibit anti-apoptotic BCL-2 proteins. The BH3 mimetics have demonstrated diverse binding specificity and efficacy in inducing apoptosis Figure 3 [ - ]. BH3 mimetics inhibit anti-apoptotic BCL-2 proteins therefore inducing both apoptosis and autophagy.
BH3 mimetics are designed to bind to anti-apoptotic BCL-2 proteins and induce apoptosis. BH3 mimetics also induce autophagy-associated cell death by preventing BCL-2 proteins from binding to the autophagy activating protein, Beclin1. One of the first small molecules developed via in silico screens was HA[ ]. HA was initially demonstrated to induce the activation of Apaf-1 and caspases in human acute myeloid leukemia cells. Clinical trials using obatoclax treatment have demonstrated success across many cancer types both independently as well as in combined therapies.
Representative clinical trials are listed in Table 2.
ABT has been shown to synergistically enhance cell death in combined treatments with chemotherapeutics and radiation[ ]. An oral form of ABT, called ABT Navitoclax , has also been developed and is also undergoing clinical trials for lymphoma, leukemia, and small cell lung cancer[ - ].
The BH3 mimetic - -gossypol is a natural polyphenol purified from the cottonseed. In addition, more potent and less toxic gossypol derivatives, such as Apogossypolone and TW, are being developed[ - ]. BH3 mimetics are designed to inhibit anti-apoptotic BCL-2 proteins and demonstrate significant therapeutic potential in clinical trials. BCL-2 has also been linked to a non-apoptotic cell death mechanism associated with autophagy, usually known as a cell survival mechanism[ ].
This discovery revealed a new role for anti-apoptotic BCL-2 protein family as anti-autophagic proteins. There are three primary types of autophagy, chaperone-mediate autophagy, microautophagy and macroautophagy[ ]. This chapter will focus on macroautophagy, referred as autophagy further in the text. Activation of autophagy induces the formation of autophagosomes that engulf damaged organelles or particles.
Eventually, the autophagsome fuses with the lysosome and degrades its interiors to provide cells the nutrients such as amino acids or fatty acids necessary for cell metabolism[ ]. Defective autophagy machinery can lead to diseases such as neurodegenerative, liver, cardiac, and muscle diseases, as well as a variety of cancers. Paradoxically, activation of autophagy upon drug treatments can induce cell death independent of or in parallel with apoptosis and necrosis.
Therefore, researchers are actively developing novel cancer therapies that aim to promote cell death by modulating autophagy pathways. Autophagy can be activated by a variety of stimuli and signaling pathways. Autophagy has also been attributed to tumor suppression. This was first demonstrated in mice with allelic loss of Beclin1, a key protein involved in inducing autophagy. Complete loss of the Beclin1 resulted in death during early embryogenesis whereas heterozygous loss of Beclin1 resulted in formations of spontaneous tumors [ , ].
Autophagy involves a conserved family of proteins known as the autophagy-related gene families ATGs. The canonical autophagy pathway in mammals occurs in a series of stages: initiation, nucleation, elongation, and degradation. All stages are regulated by a core molecular machinery Figure 4.
Cross-talk between apoptosis and autophagy. Autophagy takes place in a series of stages; initiation, nucleation, elongation, and degradation. Phagophore elongation into an autophagosome requires ATG12, LC3-I, and two ubiquitin-like protein conjugation systems. Finally, the autophagosome fuses with the lysosome and contents within the autophagosome are degraded. Beclin1 can interact with autophagy machinery at the ER and induce autophagy.
Beclin1 can also be cleaved by caspase 3 to form Beclin1-C which inhibits autophagy. However, Beclin1-C can induce apoptosis by localizing to the mitochondria facilitiating the release of apoptotic factors. Subsequently, the ULK complex localizes to the endoplasmic reticulum ER and initiates pre-autophagosome formation [ ]. ATG14L induces a translocation of the PI3KIII complex to the site of autophagosome formation and initiates the formation of an isolated membrane, also known as the phagophore[ ].
Recruitment of these proteins induces phagophore elongation [ , ]. This final step requires the endosome marker, RAB7, and a lysosomal membrane protein, LAMP2, however, the exact mechanism involved in the fusion of autophagosome and lysosomes is still unclear [ , ]. Activation of autophagy is regulated by multiple molecular pathways depending upon the stimuli Figure 4. As mentioned above, mTOR is activated under nutrient-rich environment thereby suppressing autophagy.
Starvation of growth factors and certain amino acids represses class I PI3K signaling to promote cell survival via autophagy induction [ , ]. Tumor suppressor phosphatase. Loss of PTEN occurs in multiple cancers including brain, breast, and prostate cancer [ ]. The tumor suppressor protein p53 plays a more complicated role and can induce as well as inhibit autophagy, based upon subcellular location and cellular context.
Upon exposure to DNA-damaging agents, nuclear p53 can induce autophagy by transcriptionally activating damage-regulated autophagy modulator DRAM [ ]. In addition, nuclear p53 can up-regulate ULK1 transcriptionally and directly activate autophagy[ ]. Cytoplasmic p53 has the opposite effect and can actually inhibit autophagy[ ].
High mobility group box 1 HMGB1 is a Beclin1-interacting accessory protein that assists in autophagy activation. Loss or knockdown of p53 increases the binding of HMGB1 to Beclin1 and mediates cytosolic localization of the complex to the ER [ 87 ]. As discussed above, Beclin1 is a critical inducer of autophagy. Therefore, BCL-2 anti-apoptotic proteins have dual pro-survival roles by preventing both apoptosis and autophagy-associated cell death that makes these proteins ideal chemotherapeutic targets.
Down-regulation of Beclin1 also contributes to tumorigenesis, evident in hepatocellular carcinoma, brain, colorectal, and gastric cancer [ - ]. Low expression of Beclin1 results in insufficient removal of damaged organelles. Deficient Beclin1 causes cell transformation through the accumulation of reactive oxygen species and genotoxic stress, [ ].
Furthermore, it was shown that inhibiting BCL-2 in breast cancer cells via siRNA knockdown did not induce apoptosis as expected but observed a form of autophagic cell death [ ]. The autophagic cell death was the result of combinatorial treatment with doxorubicin that lead to increased expression of Beclin1[ ].