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Simple Summary: Novel therapeutics are urgently needed for high-risk and refractory solid tumors. Clinical studies have demonstrated the safety and efficacy of PV-10 (10% rose bengal sodium) by intralesional injection in skin cancer. However, this agent has not yet been evaluated for the treatment of various adult solid tumors. The aim of our study was to test PV-10 in breast, colorectal, head and neck, and testicular cancers. Using a combination of in vitro and in vivo experiments, we found that PV-10 exhibits anti-cancer activity against a panel of human cell lines derived from these tumors. Our results support further clinical development of PV-10 for the treatment of solid tumors in adults. PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 activity and its mechanisms against phenotypically and molecularly diverse adult solid tumors had not been conducted. In a panel of human cell lines derived from breast, colorectal, head and neck, and testicular cancers, we demonstrated that PV-10 induces cytotoxicity by apoptotic and autophagic pathways involving caspase-mediated PARP cleavage, downregulation of SQSTM1/p62, and upregulation of beclin-1. Treatment with PV-10 also consistently reduced phosphorylation of WNK1, which has been implicated in cancer cell migration and autophagy inhibition. By wound healing assay, PV-10 treatment inhibited the migration of cancer cells. Finally, significant inhibition of tumor growth was also noted in tumor-bearing mice treated with PV-10 by intralesional or systemic administration. In addition to known PV-10-mediated tumor-specific cytotoxic effects, we identified the mechanisms of PV-10 and provide new insights into its effect on autophagy and metastasis. Our data provide essential mechanism-based evidence and biomarkers of activity to formulate clinical studies of PV-10 in the future. [ABSTRACT FROM AUTHOR]

Polo-like-kinase-1 (PLK-1) is a serine/threonine kinase that regulates the cell cycle and acts as an oncogene in multiple cancers, including oral squamous cell carcinoma (OSCC). The loss of PLK-1 can inhibit growth and induce apoptosis, making it an attractive therapeutic target in OSCC. We evaluated the efficacy of PLK-1 inhibitors as novel, targeted therapeutics in OSCC. PLK-1 inhibition using BI6727 (volasertib) was found to affect cell death at low nanomolar concentrations in most tested OSCC cell lines, but not in normal oral keratinocytes. In cell lines resistant to volasertib alone, pre-treatment with radiotherapy followed by volasertib reduced cell viability and induced apoptosis. The combinatorial efficacy of volasertib and radiotherapy was replicated in xenograft mouse models. These findings highlight the potential of adding PLK-1 inhibitors to adjuvant therapy regimens in OSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of high-risk neuroblastoma is poor due to its high relapse rate. To date, no effective treatment for this disease has been developed. In this study, we utilized two neuroblastoma cell lines (IMR-5 and SK-N-AS) as a model system to explore the effects of cannabinol (CBN) on neuroblastoma and elucidate the potential mechanisms of action. We reveal an inhibitory role of CBN on neuroblastoma cell proliferation, invasion, and angiogenesis through miR-34a-mediated targeting. We identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a direct target of a novel 31 nt tRNAiMet fragment tRiMetF31 generated from miR-34a-guided cleavage, highlighting the crucial role of the miR-34a/tRiMetF31/PFKFB3 axis in CBN-mediated suppression in neuroblastoma biology. High-risk neuroblastoma is an aggressive pediatric tumor. Despite great advances in neuroblastoma therapy and supportive care protocols, no curative treatment is available for most patients with this disease. Here, we uncover that CBN attenuated the cell proliferation, invasion, and angiogenesis of neuroblastoma cell lines in a dose-dependent manner via the inhibition of the AKT pathway and the upregulation of miR-34a that targets E2F1. Both miR-34a and a 31-nt tRNAiMet fragment (tRiMetF31) derived from miR-34a-guided cleavage were downregulated in 4 examined neuroblastoma cell lines inversely correlated with the levels of its direct target, the PFKFB3 protein. Moreover, ectopic tRiMetF31 suppressed proliferation, migration, and angiogenesis in the studied neuroblastoma cell lines. Conversely, tRiMetF31 knockdown promoted PFKFB3 expression, resulting in enhanced angiogenesis. Our findings reveal a suppressive role of CBN in neuroblastoma tumorigenesis, highlighting a novel and crucial miR-34a tumor suppressor network in CBN's antineuroblastoma actions. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is one of the most aggressive and common solid tumors in pediatrics. Development of effective new therapeutics for NB is in progress to help reduce mortality and morbidity of the disease, particularly in relapsed patients. The tumor suppressor protein p53 plays a critical role in multiple signaling pathways to maintain cellular hemostasis. Dysregulation of p53 protein and/or molecular aberrations have been associated with multiple human malignancies. p53 stability and protein activity is negatively regulated by the E3 ubiquitin ligase (MDM2). Thus, targeting p53-MDM2 protein-protein interaction is a feasible and promising therapeutic strategy to restore the physiological function of p53 in cancer cells. RG7112 is a highly potent and selective small molecule inhibitor, which target a unique structure located within p53 binding motif of MDM2. Methods: The efficacy of RG7112 in vitro using NB cell lines was examined. Two wild-type (WT)-p53 NB cell lines IMR5 and LAN-5, a mutant p53 cell line SK-N-BE(2), and a WT-p53/p14 deleted cell line SH-EP were employed. Results: Data showed that RG7112 significantly reduced cellular viability of IMR5 (IC50, 562 nM) and LAN-5 (IC50, 430 nM), but not SK-N-BE(2) and SH-EP cells. Further, RG7112 restores p53 and p21 protein levels in IMR5 and LAN-5 in a dose-dependent manner. RG7112 induces cell cycle arresting (60% G1 arresting) in WT-p53 cells (IMR5), but no pronounced effect observed in SK-N-BE(2). In this study, 15 different drugs in combination with RG7112 in IMR5 cell line and identified venetoclax (Bcl-2/Bcl-xL inhibitor) as a promising candidate were evaluated. Conclusions: Taken together, these findings provide initial proof-of-concept data for further investigations of RG7112 in selected subgroups of NB patients. [ABSTRACT FROM AUTHOR]

Purpose: Neuroblastoma is the most common extracranial cancer in children. Although the prognosis for low-risk neuroblastoma patients is good, the 5-year survival rates for high-risk and relapsed patients are low. The poor survival rates for these patients demonstrate the need for novel therapeutic approaches to treat this disease. PV-10 is a sterile 10% solution of Rose Bengal that has previously been shown to induce cell death in a range of adult cancers, providing the rationale for studying the activity of PV-10 against neuroblastoma in preclinical studies. Methods: The effects of PV-10 on neuroblastoma were investigated in vitro. Cytotoxicity assays were performed using the alamar blue assay on the following cell lines: SK-N-AS, SK-N-BE(2), IMR5, LAN1, SHEP, and SK-N-SH neuroblastoma cells, SK-N-MC neuroepithelioma cells, and normal primary, BJ, and WI38 fibroblasts. Phase-contrast, fluorescence, and time-lapse video microscopy; flow cytometry; and Western blotting were used to investigate the effects of PV-10 on SK-N-AS and IMR5 cells. Synergy with commonly used anticancer drugs was determined by calculation of combination indices in SK-N-AS and IMR5 cells. Mouse xenograft models of SK-N-AS and IMR5 tumors were also used to evaluate the efficacy of PV-10 in vivo. Results: In vitro preclinical data demonstrate that pharmacologically relevant concentrations of PV-10 are cytotoxic to neuroblastoma cell lines. Studies to investigate target modulation in neuroblastoma cell lines show that PV-10 disrupts lysosomes, decreases the percentage of cells in S phase, and induces apoptosis in a concentration-, time-, and cell-line-dependent manner, and we also identify agents that are synergistic with PV-10. Furthermore, experiments in xenograft mouse models show that PV-10 induces tumor regression in vivo. Conclusion: Our study provides preclinical data on the efficacy of PV-10 against neuroblastoma and provides rationale for the development of an early phase clinical trial of this agent in relapsed and refractory neuroblastoma patients. [ABSTRACT FROM AUTHOR]

Acute Myeloid Leukemia (AML) accounts for approximately one fifth of all childhood leukemia yet is responsible for a significant proportion of morbidity and mortality in this population. For this reason, research to identify novel targets for the development of effective AML therapeutics has intensified in the recent past. The THP-1 cell line, which was originally established from an infant diagnosed with AML, provides an experimental model for functional, pre-clinical therapeutics and target identification studies of AML. Here we show the expression of the voltage gated potassium channel Kv11.1 in THP-1 cells as opposed to normal hematopoietic stem cells. In addition, curcumin, a natural polyphenol derived from the plant Curcuma longa, effectively blocked Kv11.1 activity and also inhibited the proliferation of these cells. Curcumin was rapidly internalized by THP-1 cells and possibly exerts potential growth inhibitory activity by interacting with intracellular epitopes of the ion channel. Inhibition of ionic currents carried by Kv11.1 resulted in depolarization of cell membrane potential. We propose that the inhibition of Kv11.1 activity by curcumin may lead to interference with leukemic cell physiology and consequently the suppression of survival and proliferation of AML cells. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]