Combination of long-acting TRAIL and tumor cell-targeted photodynamic therapy as a novel strategy to overcome chemotherapeutic multidrug resistance and TRAIL resistance of colorectal cancer
Abstract:Chemotherapeutic multidrug resistance (MDR) is the major hindrance for clinical therapy of colorectal cancer (CRC). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with selective cytotoxicity might overcome MDR of CRC cells. Unfortunately, cross-resistance to TRAIL has been detected in many CRC cells, suggesting the need to combine TRAIL with sensitizers to combat refractory CRC. Our purpose is to explore the potential of combination therapy of TRAIL and tumor-cell targeted photodynamic therapy… Show more
“…In this regard, TRAIL as a capable chemotherapeutic ingredient has attracted considerable attention; however, TRAIL therapy has faced some limitations in the clinical setting. Although the exact mechanisms contributing to the escape from TRAIL-induced apoptosis and progress of resistance to TRAIL in tumor cells has not yet been found completely, it seems that down-regulating pro-apoptotic proteins and DR4/5, concomitant with up-regulating anti-apoptotic proteins along with activating some signaling axis plays an influential role in this regard ( 225 , 226 ). Nonetheless, it is still not elucidated whether the cellular procedures alone or in combination can stimulate resistance to TRAIL.…”
The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.
“…In this regard, TRAIL as a capable chemotherapeutic ingredient has attracted considerable attention; however, TRAIL therapy has faced some limitations in the clinical setting. Although the exact mechanisms contributing to the escape from TRAIL-induced apoptosis and progress of resistance to TRAIL in tumor cells has not yet been found completely, it seems that down-regulating pro-apoptotic proteins and DR4/5, concomitant with up-regulating anti-apoptotic proteins along with activating some signaling axis plays an influential role in this regard ( 225 , 226 ). Nonetheless, it is still not elucidated whether the cellular procedures alone or in combination can stimulate resistance to TRAIL.…”
The immune cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted rapidly evolving attention as a cancer treatment modality because of its competence to selectively eliminate tumor cells without instigating toxicity in vivo. TRAIL has revealed encouraging promise in preclinical reports in animal models as a cancer treatment option; however, the foremost constraint of the TRAIL therapy is the advancement of TRAIL resistance through a myriad of mechanisms in tumor cells. Investigations have documented that improvement of the expression of anti-apoptotic proteins and survival or proliferation involved signaling pathways concurrently suppressing the expression of pro-apoptotic proteins along with down-regulation of expression of TRAILR1 and TRAILR2, also known as death receptor 4 and 5 (DR4/5) are reliable for tumor cells resistance to TRAIL. Therefore, it seems that the development of a therapeutic approach for overcoming TRAIL resistance is of paramount importance. Studies currently have shown that combined treatment with anti-tumor agents, ranging from synthetic agents to natural products, and TRAIL could result in induction of apoptosis in TRAIL-resistant cells. Also, human mesenchymal stem/stromal cells (MSCs) engineered to generate and deliver TRAIL can provide both targeted and continued delivery of this apoptosis-inducing cytokine. Similarly, nanoparticle (NPs)-based TRAIL delivery offers novel platforms to defeat barricades to TRAIL therapeutic delivery. In the current review, we will focus on underlying mechanisms contributed to inducing resistance to TRAIL in tumor cells, and also discuss recent findings concerning the therapeutic efficacy of combined treatment of TRAIL with other antitumor compounds, and also TRAIL-delivery using human MSCs and NPs to overcome tumor cells resistance to TRAIL.
“…DR5 has been found upregulated in various types of tumors, including colorectal carcinomas, and can be exploited for selective apoptotic killing of cancer cells through caspase 8 [ 52 ]. Recent studies have shown that PDT extensively sensitizes refractory colon tumors to death signals delivered by long-acting TRAIL [ 53 ], possibly by increasing the levels of TRAIL receptors on tumor cells. Furthermore, the increased levels of the BID transcripts evidenced by us may sustain the connection of death receptor signaling to the mitochondrial apoptotic machinery [ 54 ].…”
Photodynamic therapy (PDT), a highly targeted therapy with acceptable side effects, has emerged as a promising therapeutic option in oncologic pathology. One of the issues that needs to be addressed is related to the complex network of cellular responses developed by tumor cells in response to PDT. In this context, this study aims to characterize in vitro the stressors and the corresponding cellular responses triggered by PDT in the human colon carcinoma HT29 cell line, using a new asymmetric porphyrin derivative (P2.2) as a photosensitizer. Besides investigating the ability of P2.2-PDT to reduce the number of viable tumor cells at various P2.2 concentrations and fluences of the activating light, we assessed, using qRT-PCR, the expression levels of 84 genes critically involved in the stress response of PDT-treated cells. Results showed a fluence-dependent decrease of viable tumor cells at 24 h post-PDT, with few cells that seem to escape from PDT. We highlighted following P2.2-PDT the concomitant activation of particular cellular responses to oxidative stress, hypoxia, DNA damage and unfolded protein responses and inflammation. A web of inter-connected stressors was induced by P2.2-PDT, which underlies cell death but also elicits protective mechanisms that may delay tumor cell death or even defend these cells against the deleterious effects of PDT.
“…The high affinity (pM to nM range) of the affibody molecules to their targets, their small size (in vivo this results in fast clearance from the circulation with mostly renal excretion), and good tumor penetration make them ideal targeting agents to increase the concentration of the photosensitizers in the tumor site, while limiting toxicity in normal tissues. The photosensitizer IR700DX (IR700) was conjugated to the ZEGFR affibody (Ze), which has high specificity and affinity for EGFR to produce the Ze-IR700 conjugate [229] (Table 12). Ze-IR700 conjugates bind to EGFR-overexpressing cells and are uptaken, localizing predominantly in lysosomes [229].…”
Section: Anti Egfr-affibodiesmentioning
confidence: 99%
“…The photosensitizer IR700DX (IR700) was conjugated to the ZEGFR affibody (Ze), which has high specificity and affinity for EGFR to produce the Ze-IR700 conjugate [229] (Table 12). Ze-IR700 conjugates bind to EGFR-overexpressing cells and are uptaken, localizing predominantly in lysosomes [229]. The in vitro phototoxicity of the Ze-IR700 conjugate was demonstrated, suggesting that PDT treatment predominantly induces lysosome-associated apoptosis [229].…”
The epidermal growth factor receptor (EGFR) plays a pivotal role in the proliferation and metastatization of cancer cells. Aberrancies in the expression and activation of EGFR are hallmarks of many human malignancies. As such, EGFR-targeted therapies hold significant potential for the cure of cancers. In recent years, photodynamic therapy (PDT) has gained increased interest as a non-invasive cancer treatment. In PDT, a photosensitizer is excited by light to produce reactive oxygen species, resulting in local cytotoxicity. One of the critical aspects of PDT is to selectively transport enough photosensitizers to the tumors environment. Accordingly, an increasing number of strategies have been devised to foster EGFR-targeted PDT. Herein, we review the recent nanobiotechnological advancements that combine the promise of PDT with EGFR-targeted molecular cancer therapy. We recapitulate the chemistry of the sensitizers and their modes of action in PDT, and summarize the advantages and pitfalls of different targeting moieties, highlighting future perspectives for EGFR-targeted photodynamic treatment of cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.