The synergistic mechanisms of propofol with cisplatin or doxorubicin in human ovarian cancer cells.

BACKGROUND: Most ovarian cancer cases are diagnosed at an advanced stage, leading to poor outcomes and a relatively low 5-year survival rate. While tumor resection in the early stages can be highly effective, recurrence following primary treatment remains a significant cause of mortality. Propofol is a commonly used intravenous anesthetic agent in cancer resection surgery. Previous research has shown that propofol anesthesia was associated with improved survival in patients undergoing elective surgery for epithelial ovarian cancer. However, the underlying antitumor mechanisms are not yet fully understood. METHODS: This study aimed to uncover the antitumor properties of propofol alone and combined with cisplatin or doxorubicin, in human SKOV3 and OVCAR3 ovarian cancer cells. We applied flowcytometry analysis for mitochondrial membrane potential, apoptosis, and autophagy, colony formation, migration, and western blotting analysis. RESULTS: Given that chemotherapy is a primary clinical approach for managing advanced and recurrent ovarian cancer, it is essential to address the limitations of current chemotherapy, particularly in the use of cisplatin and doxorubicin, which are often constrained by their side effects and the development of resistance. First of all, propofol acted synergistically with cisplatin and doxorubicin in SKOV3 cells. Moreover, our data further showed that propofol suppressed colony formation, disrupted mitochondrial membrane potential, and induced apoptosis and autophagy in SKOV3 and OVCAR3 cells. Finally, the effects of combined propofol with cisplatin or doxorubicin on mitochondrial membrane potential, apoptosis, autophagy, and epithelial-mesenchymal transition were different in SKOV3 and OVCAR3 cells, depending on the p53 status. CONCLUSION: In summary, repurposing propofol could provide novel insights into the existing chemotherapy strategies for ovarian cancer. It holds promise for overcoming resistance to cisplatin or doxorubicin and may potentially reduce the required chemotherapy dosages and associated side effects, thus improving treatment outcomes.

Combinatory Effect of Pequi Oil (Caryocar brasiliense)-Based Nanoemulsions Associated to Docetaxel and Anacardic Acid (Anacardium occidentale) in Triple-Negative Breast Cancer Cells In Vitro.

Combination therapy integrated with nanotechnology offers a promising alternative for breast cancer treatment. The inclusion of pequi oil, anacardic acid (AA), and docetaxel (DTX) in a nanoemulsion can amplify the antitumor effects of each molecule while reducing adverse effects. Therefore, the study aims to develop pequi oil-based nanoemulsions (PeNE) containing DTX (PDTX) or AA (PAA) and to evaluate their cytotoxicity against triple-negative breast cancer cells (4T1) in vitro. The PeNE without and with AA (PAA) and DTX (PDTX) were prepared by sonication and characterized by ZetaSizer® and electronic transmission microscopy. Viability testing and combination index (CI) were determined by MTT and Chou-Talalay methods, respectively. Flow cytometry was employed to investigate the effects of the formulations on cell structures. PeNE, PDTX, and PAA showed hydrodynamic diameter < 200 nm and a polydispersity index (PdI) of 0.3. The association PDTX + PAA induced a greater decrease in cell viability (~70%, p < 0.0001) and additive effect (CI < 1). In parallel, an association of the DTX + AA molecules led to antagonism (CI > 1). Additionally, PDTX + PAA induced an expressive morphological change, a major change in lysosome membrane permeation and mitochondria membrane permeation, cell cycle blockage in G2/M, and phosphatidylserine exposure. The study highlights the successful use of pequi oil nanoemulsions as delivery systems for DTX and AA, which enhances their antitumor effects against breast cancer cells. This nanotechnological approach shows significant potential for the treatment of triple-negative breast cancer.

Combinatory effect of ALA-PDT and itraconazole in the treatment of cutaneous protothecosis.

BACKGROUND: As a rare subcutaneous infection, protothecosis is easily misdiagnosed. Similar to other subcutaneous infection, there is no unified standard for treatment, for cases not suitable for surgery, clinicians often use antifungal drugs based on their experience, and the course of treatment varies from several months to several years. Based on the fact that there are few relevant materials and researches on photodynamic therapy (PDT), we conducted a study based on a clinical case that used oral itraconazole combined with 5-aminolevylinic acid photodynamic therapy (ALA-PDT) to treat a patient with cutaneous protothecosis caused by Prototheca wicherhamii. METHODS: Different concentrations of ALA and different light doses were used to investigate the effects of ALA-PDT on the growth inhibition of P. wickerhamii in vitro with Colony-counting Methods. And we used transmission electron microscopy (TEM) to visualize the structural changes and the effects of ALA-PDT treating on cellular structures of the P. wickerhamii. Futher, we performed the susceptibility test of P. wickerhamii to itraconazole before and after ALA-PDT in vitro. RESULTS: We have successfully treated a patient with cutaneous protothecosis caused by P. wickerhamii by using combination therapy in a total of 9-week course of treatment. In vitro, ALA-PDT can inhibit the growth of P. wickerhamii when the ALA concentration was 5 mg/mL (P < 0.01), and this effect became stronger as the concentration of ALA or light dose is increased. Using TEM, we confirmed that ALA-PDT can disrupt the cell wall structure and partition structure of P. wickerhamii, which may contribute to its inhibitory effect. Further studies showed that the MIC of itraconazole for P. wickerhamii was decreased after ALA-PDT. CONCLUSIONS: ALA-PDT combined with oral itraconazole can be used to treat cutaneous protothecosis. Accordingly, ALA-PDT can destroy the cell wall and partition structure of P. wickerhamii leading to an inhibitory effect on it in vitro, and the effect is enhanced with the increase of ALA concentration and light dose. Also, the sensitivity of P. wickerhamii to itraconazole is observed increased after ALA-PDT. So our study provides a theoretical basis for the promising treatment against cutaneus protothecosis.

Therapeutic Effects of IL-1RA, M2 Cells, and Their Synergistic Impact on a Mouse Model of Rheumatoid Arthritis.

Purpose: Rheumatoid arthritis (RA) is a type of autoimmune disease that results in chronic inflammation of the joint synovial tissue, leading to joint damage and significant disability. Despite ongoing research, the exact cause of RA remains unclear, and current treatments have limitations. This study explores the potential of utilizing interleukin-1 receptor antagonist (IL-1RA) and anti-inflammatory macrophages polarized in the vicinity of the supernatant from allogeneic mesenchymal stem cells (MSCs) as a novel therapeutic approach for RA. Methods: An expression cassette containing the IL-1RA gene was constructed and expressed in E. coli BL21. The resulting protein was purified and stabilized for use in in vivo experiments. Bone marrow MSCs were isolated and used to produce anti-inflammatory M2 macrophages from the isolated peripheral blood monocytes. The macrophages were then used to treat mice with RA induced by collagen type II. Results: The combination of IL-1RA and M2 macrophages improved clinical and histopathological symptoms of the disease, reduced levels of inflammatory factors, and modulated the immune system in the treated mouse groups. The results showed that this combinatory therapy had a synergistic effect for RA treatment. Conclusion: The simultaneous use of IL-1RA and M2 cells could be a promising approach for the treatment of RA. This combinatory therapy has the potential to improve the disease and decrease the severity of inflammation in patients with RA.

Enhancing CAR T cells function: role of immunomodulators in cancer immunotherapy.

CAR T-cell therapy is a promising immunotherapy, providing successful results for cancer patients who are unresponsive to standard and traditional therapeutic approaches. However, there are limiting factors which create a hurdle in the therapy performing its role optimally. CAR T cells get exhausted, produce active antitumor responses, and might even produce toxic reactions. Specifically, in the case of solid tumors, chimeric antigen receptor T (CAR-T) cells fail to produce the desired outcomes. Then, the need to use supplementary agents such as immune system modifying immunomodulatory agents comes into play. A series of the literature was studied to evaluate the role of immunomodulators including a phytochemical, Food and Drug Administration (FDA)-approved targeted drugs, and ILs in support of their achievements in boosting the efficiency of CAR-T cell therapy. Some of the most promising out of them are reported in this article. It is expected that by using the right combinations of immunotherapy, immunomodulators, and traditional cancer treatments, the best possible cancer defying results may be produced in the future.

Ferroptosis resistance in cancer cells: nanoparticles for combination therapy as a solution.

Ferroptosis is a form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. Ferroptosis is currently proposed as one of the most promising means of combating tumor resistance. Nevertheless, the problem of ferroptosis resistance in certain cancer cells has been identified. This review first, investigates the mechanisms of ferroptosis induction in cancer cells. Next, the problem of cancer cell resistance to ferroptosis, as well as the underlying mechanisms is discussed. Recently discovered ferroptosis-suppressing biomarkers have been described. The various types of nanoparticles that can induce ferroptosis are also discussed. Given the ability of nanoparticles to combine multiple agents, this review proposes nanoparticle-based ferroptosis cell death as a viable method of circumventing this resistance. This review suggests combining ferroptosis with other forms of cell death, such as apoptosis, cuproptosis and autophagy. It also suggests combining ferroptosis with immunotherapy.

Overcoming antibiotic resistance: non-thermal plasma and antibiotics combination inhibits important pathogens.

Antibiotic resistance (ATBR) is increasing every year as the overuse of antibiotics (ATBs) and the lack of newly emerging antimicrobial agents lead to an efficient pathogen escape from ATBs action. This trend is alarming and the World Health Organization warned in 2021 that ATBR could become the leading cause of death worldwide by 2050. The development of novel ATBs is not fast enough considering the situation, and alternative strategies are therefore urgently required. One such alternative may be the use of non-thermal plasma (NTP), a well-established antimicrobial agent actively used in a growing number of medical fields. Despite its efficiency, NTP alone is not always sufficient to completely eliminate pathogens. However, NTP combined with ATBs is more potent and evidence has been emerging over the last few years proving this is a robust and highly effective strategy to fight resistant pathogens. This minireview summarizes experimental research addressing the potential of the NTP-ATBs combination, particularly for inhibiting planktonic and biofilm growth and treating infections in mouse models caused by methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa. The published studies highlight this combination as a promising solution to emerging ATBR, and further research is therefore highly desirable.

A NIR-Activated and Mild-Temperature-Sensitive Nanoplatform with an HSP90 Inhibitor for Combinatory Chemotherapy and Mild Photothermal Therapy in Cancel Cells.

Mild photothermal therapy (PTT) shows great potential to treat cancers while avoiding unwanted damage to surrounding normal cells. However, the efficacy of mild PTT is normally moderate because of the low hyperthermia temperature and limited light penetration depth. Chemotherapy has unlimited penetration but often suffers from unsatisfactory efficacy in view of the occurrence of drug resistance, suboptimal drug delivery and release profile. As a result, the combinatory of chemotherapy and mild PTT would integrate their advantages and overcome the shortcomings. Herein, we synthesized an NIR-activatable and mild-temperature-sensitive nanoplatform (BDPII-gel@TSL) composed of temperature-sensitive liposomes (TSL), heat shock protein 90 (HSP90) inhibitor (geldanamycin) and photothermal agent (BDPII), for dual chemotherapy and mild PTT in cancer cells. BDPII, constructed with donor-acceptor moieties, acts as an excellent near-infrared (NIR) photothermal agent (PTA) with a high photothermal conversion efficiency (80.75%). BDPII-containing TSLs efficiently produce a mild hyperthermia effect (42 °C) under laser irradiation (808 nm, 0.5 W cm-2). Importantly, the phase transformation of TSL leads to burst release of geldanamycin from BDPII-gel@TSL, and this contributes to down-regulation of the overexpression of HSP90, ensuring efficient inhibition of cancer cell growth. This research provides a dual-sensitive synergistic therapeutic strategy for cancer cell treatment.

Cascade Amplification of Pyroptosis and Apoptosis for Cancer Therapy through a Black Phosphorous-Doped Thermosensitive Hydrogel.

Cell pyroptosis has a reciprocal relationship with various cancer treatment modalities such as chemotherapy. However, the tumor microenvironment, characterized by hypoxia, substantially restricts the development and application of tumor therapies that integrate cell pyroptosis. Therefore, the cascade amplification of oxidative stress by interfering with redox homeostasis in tumors may be a promising approach. In this study, black phosphorus (BP) nanosheets and a glutathione peroxidase 4 inhibitor (RSL3) were coloaded into a thermosensitive PDLLA-PEG-PDLLA (PLEL) hydrogel (RSL3/BP@PLEL). Owing to the photothermal property of BP nanosheets, the RSL3/BP@PLEL hydrogel may trigger the release of loaded drugs in a more controllable and on-demand manner. Investigation of the antitumor effect in a mouse liver tumor model demonstrated that local injection of the hydrogel formulation in combination with near infrared laser irradiation could efficiently suppress tumor growth by interfering with the redox balance in tumors. Mechanistic study indicated that the combined treatment of photothermal therapy and glutathione depletion based on this hydrogel efficiently induced cell pyroptosis through both caspase-1/GSDMD and caspase-3/GSDME pathways, thereby triggering the repolarization of tumor-associated macrophages from M2 to M1. Overall, we developed a biocompatible and biodegradable hydrogel formulation for application in combination cancer treatment, providing a new platform for enhancing the efficacy of cancer therapy by amplifying cell pyroptosis and apoptosis.

Recent advances in the combination of cellular therapy with stem cells and nanoparticles after a spinal cord injury.

Background: Currently, combined therapies could help to reduce long-term sequelae of spinal cord injury (SCI); stem cell therapy at the site of injury in combination with other therapies has shown very promising results that can be transferred to the clinical field. Nanoparticles (NPs) are versatile technologies with applications to medical research for treatments of SCI since they could deliver therapeutic molecules to the target tissue and may help to reduce the side effects of non-targeted therapies. This article's purpose is to analyze and concisely describe the diverse cellular therapies in combination with NPs and their regenerative effect after SCI. Methods: We reviewed the literature related to combinatory therapy for motor impairment following SCI that has been published by Web of Science, Scopus, EBSCO host, and PubMed databases. The research covers the databases from 2001 to December 2022. Result: Animal models of SCI have shown that the combination of NPs plus stem cells has a positive impact on neuroprotection and neuroregeneration. Further research is required to better understand the effects and benefits of SCI on a clinical level; therefore, it is necessary to find and select the most effective molecules that are capable of exacerbating the neurorestorative effects of the different stem cells and then try them out on patients after SCI. On the other hand, we consider that synthetic polymers such as poly [lactic-co-glycolic acid] (PLGA) could be a candidate for the design of the first therapeutic strategy that combines NPs with stem cells in patients with SCI. The reasons for the selection are that PLGA has shown important advantages over other NPs, such as being biodegradable, having low toxicity levels, and high biocompatibility; In addition, researchers could control the release time and the biodegradation kinetics, and most importantly, it could be used as NMs on other clinical pathologies (12 studies on www.clinicaltrials.gov) and has been approved by the Federal Food, Drug, and Cosmetic Act (FDA). Conclusion: The use of cellular therapy and NPs may be a worthwhile alternative for SCI therapy; however, it is expected that the data obtained from interventions after SCI reflect an important variability of molecules combined with NPs. Therefore, it is necessary to properly define the limits of this research to be able to continue to work on the same line. Consequently, the selection of a specific therapeutic molecule and type of NPs plus stem cells are crucial to evaluate its application in clinical trials.

Stimuli-activatable PROTACs for precise protein degradation and cancer therapy.

The proteolysis targeting chimeras (PROTACs) approach has attracted extensive attention in the past decade, which represents an emerging therapeutic modality with the potential to tackle disease-causing proteins that are historically challengeable for conventional small molecular inhibitors. PROTAC harnesses the endogenic E3 ubiquitin ligase to degrade protein of interest (POI) via ubiquitin-proteasome system in a cycle-catalytic manner. The event-driven pharmacology of PROTAC is poised to pursue those targets that are conventionally undruggable, which enormously extends the space of drug development. Furthermore, PROTAC has the potential to address drug resistance of small molecular inhibitors by degrading the whole POI. Nevertheless, PROTACs display high-efficiency and always-on properties to degrade POI, they may cause severe side effects due to an "on-target but off-tissue" protein degradation profile at the undesirable tissues and cells. Given that, the stimuli-activatable PROTAC prodrugs have been recently exploited to confine precise protein degradation of the favorable targets, which may conquer the adverse effects of PROTAC due to uncontrollable protein degradation. Herein, we summarized the cutting-edge advances of the stimuli-activatable PROTAC prodrugs. We also overviewed the progress of PROTAC prodrug-based nanomedicine to improve PROTAC delivery to the tumors and precise POI degradation in the targeted cells.

Evodiamine as an anticancer agent: a comprehensive review on its therapeutic application, pharmacokinetic, toxicity, and metabolism in various cancers.

Evodiamine is a major alkaloid component found in the fruit of Evodia rutaecarpa. It shows the anti-proliferative potential against a wide range of cancers by suppressing cell growth, invasion, and metastasis and inducing apoptosis both in vitro and in vivo. Evodiamine shows its anticancer potential by modulating aberrant signaling pathways. Additionally, the review focuses on several therapeutic implications of evodiamine, such as epigenetic modification, cancer stem cells, and epithelial to mesenchymal transition. Moreover, combinatory drug therapeutics along with evodiamine enhances the anticancer efficacy of chemotherapeutic drugs in various cancers by overcoming the chemo resistance and radio resistance shown by cancer cells. It has been widely used in preclinical trials in animal models, exhibiting very negligible side effects against normal cells and effective against cancer cells. The pharmacokinetic and pharmacodynamics-based collaborations of evodiamine are also included. Due to its poor bioavailability, synthetic analogs of evodiamine and its nano capsule have been formulated to enhance its bioavailability and reduce toxicity. In addition, this review summarizes the ongoing research on the mechanisms behind the antitumor potential of evodiamine, which proposes an exciting future for such interests in cancer biology.

Redox Dyshomeostasis with Dual Stimuli-Activatable Dihydroartemisinin Nanoparticles to Potentiate Ferroptotic Therapy of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to conventional therapies, including chemo-, radio-, and immunotherapy. In this study, it is first determined that a combination of dihydroartemisinin (DHA) and RSL-3 (a glutathione peroxidase 4 (GPX4) inhibitor) markedly induced ferroptosis of PDAC tumor cells. A mechanistic study revealed that DHA can react with iron ions to generate carbon radicals and deplete intracellular glutathione, thereby cumulatively triggering the lipid peroxidation of tumor cells with RSL-3-mediated GPX4 inhibition. A DHA-conjugated amphiphilic copolymer is subsequently synthesized, and intracellular acidity and oxidation dual-responsive DHA nanoparticles are further engineered for the tumor-specific co-delivery of DHA and RSL-3. The resultant nanoparticles (PDBA@RSL-3) efficiently induce ferroptosis of tumor cells in the Panc02 tumor-bearing immune-deficient mouse model, and elicit T-cell-based antitumor immunity in the immune-competent mouse model. The combination of PDBA@RSL-3 nanoparticles and programmed death ligand 1 blockade therapy efficiently inhibits PDAC tumor growth in the immune-competent mouse models. This study may provide novel insights for treatment of PDAC with ferroptosis-based immunotherapy.

Combinatory therapy of MRP1-targeted photoimmunotherapy and liposomal doxorubicin promotes the antitumor effect for chemoresistant small cell lung cancer.

Small cell lung cancer (SCLC), considered a mortal recalcitrant cancer, is a severe healthcare issue because of its poor prognosis, early metastasis, drug resistance and limited clinical treatment options. In our previous study, we established a MRP1-targeted antibody-IR700 system (Mab-IR700) for near infrared photoimmunotherapy (NIR-PIT) which exhibited a promising therapeutic effect on drug resistant H69AR cells both in vitro and in vivo, though the tumor growth suppression effect did not last long with a single round of PIT treatment. To achieve a better anticancer effect, we have combined Mab-IR700-mediated NIR-PIT with liposomal doxorubicin (Doxil®) and investigated the in vitro and in vivo cytotoxicity by using a H69AR/3T3 cell co-culture model in which 3T3 cells were used to mimic stromal cells. Cytotoxicity experiments demonstrated the specificity of Mab-IR700 to H69AR cells, while cytotoxicity and flow cytometry experiments confirmed that H69AR cells were doxorubicin-resistant. Compared with Mab-IR700-mediated PIT or Doxil-mediated chemotherapy, the combination therapy exhibited the best cell killing effect in vitro and superior tumor growth inhibition and survival prolongation effect in vivo. Super enhanced permeability and retention (SUPR) effect was observed in both co-culture spheroids and tumor-bearing mice. Owing to an approximately 9-fold greater accumulation of Doxil within the tumors, NIR-PIT combined with Doxil resulted in enhanced antitumor effects compared to NIR-PIT alone. This photoimmunochemotherapy is a practical strategy for the treatment of chemoresistant SCLC and should be further investigated for clinical translation.

Metal-Based Nanostructured Therapeutic Strategies for Glioblastoma Treatment-An Update.

Glioblastoma (GBM) is the most commonly diagnosed and most lethal primary malignant brain tumor in adults. Standard treatments are ineffective, and despite promising results obtained in early phases of experimental clinical trials, the prognosis of GBM remains unfavorable. Therefore, there is need for exploration and development of innovative methods that aim to establish new therapies or increase the effectiveness of existing therapies. One of the most exciting new strategies enabling combinatory treatment is the usage of nanocarriers loaded with chemotherapeutics and/or other anticancer compounds. Nanocarriers exhibit unique properties in antitumor therapy, as they allow highly efficient drug transport into cells and sustained intracellular accumulation of the delivered cargo. They can be infused into and are retained by GBM tumors, and potentially can bypass the blood-brain barrier. One of the most promising and extensively studied groups of nanostructured therapeutics are metal-based nanoparticles. These theranostic nanocarriers demonstrate relatively low toxicity, thus they might be applied for both diagnosis and therapy. In this article, we provide an update on metal-based nanostructured constructs in the treatment of GBM. We focus on the interaction of metal nanoparticles with various forms of electromagnetic radiation for use in photothermal, photodynamic, magnetic hyperthermia and ionizing radiation sensitization applications.

Photodynamic therapy and combinatory treatments for the control of biofilm-associated infections.

The advent of antimicrobial resistance has added considerable impact to infectious diseases both in the number of infections and healthcare costs. Furthermore, the relentless emergence of multidrug-resistant bacteria, particularly in the biofilm state, has made mandatory the discovery of new alternative antimicrobial therapies that are capable to eradicate resistant bacteria and impair the development of new forms of resistance. Amongst the therapeutic strategies for treating biofilms, antimicrobial photodynamic therapy (aPDT) has shown great potential in inactivating several clinically relevant micro-organisms, including antibiotic-resistant 'priority bacteria' declared by the WHO as critical pathogens. Its antimicrobial effect is centred on the basis that harmless low-intensity light stimulates a non-toxic dye named photosensitizer, triggering the production of reactive oxygen species upon photostimulation. In addition, combination therapies of aPDT with other antimicrobial agents (e.g. antibiotics) have also drawn considerable attention, as it is a multi-target strategy. Therefore, the present review highlights the recent advances of aPDT against biofilms, also covering progress on combination therapy.

Sensitizing TRAIL response via differential modulation of anti- and pro-apoptotic factors by AZD5582 combined with ER nanosomal TRAIL in neuroblastoma.

Neuroblastoma is a metastatic brain tumor particularly common in children. The cure rate is below 50% for patients of high-risk condition. Novel therapeutic agents and approaches are needed to improve the cure rate. Tumor necrosis factor-related and apoptosis-inducing ligand (TRAIL) is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells. Unfortunately, the common TRAIL resistance in cancers has hampered the clinical application of the ligand. Previously we prepared a novel TRAIL-armed ER derived nanosomal agent (ERN-T) that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins (IAPs), AZD5582. However, how AZD5582 sensitizes cancer cells to ERN-T remains not well understood. In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma, aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T. The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5Y when combined with AZD5582 whilst sparing normal cells. The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5Y but not in normal skin fibroblasts (NSFs). Importantly we discovered that TRAIL sensitization in SH-SY5Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP, MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5 (DR5) by the cotreatment of ERN-T and AZD5582. In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5Y xenograft neuroblastoma in nude mice. In conclusion, we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy, which is highly effective and safe for neuroblastoma.

Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma-A Comprehensive Update.

Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment regimens are probably less likely to induce drug resistance, a special focus will be on the combination of ALK inhibitors with drugs that either target downstream signalling pathways or that affect the survival and proliferation of cancer cells in general.

Combination Therapy of Novel Oncolytic Adenovirus with Anti-PD1 Resulted in Enhanced Anti-Cancer Effect in Syngeneic Immunocompetent Melanoma Mouse Model.

Malignant melanoma, an aggressive form of skin cancer, has a low five-year survival rate in patients with advanced disease. Immunotherapy represents a promising approach to improve survival rates among patients at advanced stage. Herein, the aim of the study was to design and produce, by using engineering tools, a novel oncolytic adenovirus AdV-D24- inducible co-stimulator ligand (ICOSL)-CD40L expressing potent co-stimulatory molecules enhancing clinical efficacy through the modulation of anti-cancer immune responses. Firstly, we demonstrated the vector's identity and genetic stability by restriction enzyme assay and sequencing, then, by performing in vitro and in vivo pre-clinical studies we explored the anti-cancer efficacy of the virus alone or in combination with anti PD-1 inhibitor in human melanoma cell lines, i.e., MUG Mel-1 and MUG Mel-2, and in immunocompetent C57BL/6 melanoma B16V mouse model. We showed that both monotherapy and combination approaches exhibit enhanced anti-cancer ability and immunogenic cell death in in vitro settings. Furthermore, AdV-D24-ICOSL-CD40L combined with anti PD-1 revealed a fall in tumor volume and 100% survival in in vivo context, thus suggesting enhanced efficacy and survival via complementary anti-cancer properties of those agents in melanoma therapy. Collectively, the novel oncolytic vector AdV-D24-ICOSL-CD40L alone or in combination with anticancer drugs, such as check point inhibitors, may open novel therapeutic perspectives for the treatment of melanoma.