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In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood–brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.

Celyvir is an advanced therapy medicine, consisting of mesenchymal stem cells (MSCs) containing the oncolytic virus ICOVIR 5. This paper sets out a dynamic system which attempts to capture the fundamental relationships between cancer, the immune system and adenoviruses. Two forms of treatment were studied: continuous and periodic, the second being closer to the real situation. In the analysis of the first model, in addition to identifying the critical points, their properties and bifurcation points, a number of numerical simulations were carried out. It has thus been shown that there are bistability regimes in which Celyvir can produce an equilibrium of tumor progression, or even freedom from tumor. A sensitivity analysis was also performed to determine which parameters are most important in the system. Subsequently, an optimal control problem with nonlinear objective functional has been formulated, where the therapeutic goal is not only to minimize the size of the tumor cell population and the total cost of treatment, but also to prevent the tumor from reaching a critical size. It has been shown that the optimal control is bang–bang. With the second model, a threshold value of viral load has been identified at which the success of the treatment could be ensured. It is clear in both models that a low viral load would lead to relapse of the disease. Finally, it is shown that a periodic bang–bang regime should be used to optimize treatment with Celyvir.

Neuroblastoma (NB) is one of the most common extracranial malignancies in children, accounting for 7–8% of childhood malignancies. As one of the main treatments for NB, radiotherapy is limited by various factors in clinics, such as the hypoxia microenvironment in tumor and serious side effects. Herein, we synthesized a kind of nanoscale coordination polymer denoted as Hf@DAP nanoparticles composed of hafnium ion (Hf${}^{4+})$ and 2,6-diaminopimelic acid (DAP), one of bacterial derivatives. From the image of transmission electron microscope (TEM), nanoparticles had uniform dispersion. Furthermore, the hydrodynamic diameter measured by dynamic light scattering method was about 190 nm. In this structure, the Hf${}^{4+}$ can enhance radiotherapy by effectively enhancing the function of X-ray, and the DAP was a biocompatible ligand for fabricating the nanoscale coordination nanoparticles. Furthermore, Hf@DAP nanoparticles were stable in various mediums and exhibited favorable biocompatibility in various cell lines in vitro. Cell viabilities were tested by cell counting kit (CCK-8) in vitro. There was no obvious cytotoxicity to normal cells, including NIH3T3, RAW264.7, and HUVECs, after incubation with Hf@DAP nanoparticles, indicating biocompatibilities of Hf@DAP nanoparticles. Additionally, a significantly enhanced radiotherapy effect was observed in the N2a cells, a kind of NB cell line, pretreated with Hf@DAP nanoparticles in vitro. The in vivo tumor growth was obviously inhibited in the mice with the combined therapy of Hf@DAP nanoparticles and X-ray, compared with PBS group, Hf@DAP group, and X-ray group. Furthermore, the survival time of the mice in the combined group was significantly prolonged, compared with PBS group. In addition, tissues structures of main organs, such as the lung, liver, spleen, and kidney in these mice, were ordered without the influence of Hf@DAP nanoparticles. Thus, this work proposed a potential radio-sensitizer for further clinical radiotherapy with limited side effects and high efficiency.

The poor prognosis for patients with metastatic cancer and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Dosage of systemically administered chemotherapeutic agents is limited by the toxicity to normal tissues, often precluding achievement of therapeutic indices of sufficient levels to affect complete cures. Malignant brain tumors pose further limitations to available therapies due to the infiltrative nature of the tumor cells throughout the brain and the presence of the blood–brain barrier. Novel anti-cancer treatment approaches must be more tumor-localized and tumor cell-selective to improve effectiveness and clinical outcome.

Neural stem (and/or progenitor) cells (NSCs) display inherent tumor-tropic properties that can be exploited for targeted delivery of anti-cancer agents to invasive and metastatic tumors. We and others have previously demonstrated that NSCs can deliver bioactive therapeutic agents to elicit a significant anti-tumor response in animal models of intracranial glioma, medulloblastoma and melanoma brain metastases. Recent studies demonstrate retention of tumor-tropic properties when NSCs are injected into the peripheral vasculature, localizing to multiple tumor sites in animal models of disseminated neuroblastoma and orthotopic breast carcinoma, with little accumulation in normal tissues. We postulate that this NSC-mediated, tumor-selective approach can maximize local concentrations of anti-cancer agents to tumor foci, while minimizing toxicity to normal tissues. This would potentially achieve therapeutic indices sufficient to eradicate invasive tumors that are otherwise lethal.

Several well-characterized immortalized murine and human NSC lines have been extensively studied for the determination of their therapeutic potential in animal tumor models of glioblastoma, melanoma brain metastases, medulloblastoma, and disseminated neuroblastoma. In all invasive and metastatic solid tumor models, 70–90% therapeutic efficacy was achieved as measured by increased long-term survival or decreased tumor burden. Other studies in the literature demonstrated the achievement of similar results with nonimmortalized NSC pools modified with various therapeutic genes, further verifying the NSC tumor tropism phenomenon. However, these pools are more difficult to keep consistent over time and passage, adding more variability to pre-clinical trials and more difficulty in creating uniform master cell banks for clinical trials.

We suggest that using a stable, sustainable and easily expandable clonal NSC line will circumvent the problems associated with characterization, senescence, and replenishment sources of primary stem cell pools. It would also allow for cost-effective and accessible patient trials. At the very least, such NSC lines can serve in proof-of-concept pre-clinical studies, where tumor types and therapeutic regimens are being tested. Preliminary biodistribution studies indicate that one such immortalized human NSC line (HB1.F3) is safe, non-immunogenic and non-tumorigenic. Furthermore, these cells retain their tumor-tropic property when modified to express therapeutic transgenes. Genomic stability and retention of tumor-tropic properties over time and passage has also been confirmed, making it a very promising line for clinical trials.

Regardless of which NSCs move towards therapeutic cancer trials, safety and feasibility would be best assessed first in patients with no alternative treatments, such as recurrent high-grade gliomas. These aggressive tumor cells infiltrate normal brain, and are not readily treatable by resection, irradiation, chemotherapy or gene therapy. In rodent models of orthotopic human brain tumors, it has been demonstrated that HB1.F3 NSCs can selectively target invasive tumor cells and distant micro tumor foci, achieving therapeutic efficacy with an enzyme/prodrug strategy. This serves as one example of many different anti-cancer agents that could be similarly delivered to tumor sites throughout the body.