Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, DNMT1 functions in self-renewal and maintenance of cancer stem cell in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anticancer agents. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represent a promising approach for the prevention and treatment of many cancers.

Malignant tumors contain heterogeneous populations of cells in various states of proliferation and differentiation. The presence of cancer stem or initiating cells is a well-established concept wherein quiescent and poorly differentiated cells within a tumor mass contribute to drug resistance, and under permissive conditions, are responsible for tumor recurrence and metastasis. A number of studies have identified molecular markers that are characteristic of tissue-specific cancer stem cells (CSCs). Isolation of CSCs has enabled studies on the metabolic status of CSCs. As metabolic plasticity is a hallmark of cancer cell adaptation, the intricacies of CSC metabolism and their phenotypic behavior are critical areas of research. Unlike normal stem cells, which rely heavily on oxidative phosphorylation (OXPHOS) as their primary source of energy, or cancer cells, which are primarily glycolytic, CSCs demonstrate a unique metabolic flexibility. CSCs can switch between OXPHOS and glycolysis in the presence of oxygen to maintain homeostasis and, thereby, promote tumor growth. Here, we review key factors that impact CSC metabolic phenotype including heterogeneity of CSCs across different histologic tumor types, tissue-specific variations, tumor microenvironment, and CSC niche. Furthermore, we discuss how targeting key players of glycolytic and mitochondrial pathways has shown promising results in cancer eradication and attenuation of disease recurrence in preclinical models. In addition, we highlight studies on other potential therapeutic targets including complex interactions within the microenvironment and cellular communications in the CSC niche to interfere with CSC growth, resistance, and metastasis.

Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate) in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival. Hence, there is a substantial need for new therapies. The inability to control the metastatic progression of this localized cancer stems from a lack of complete knowledge of the biology of osteosarcoma. Consequently, there has been an aggressive undertaking of scientific investigation of various signaling pathways that could be instrumental in understanding the pathogenesis of osteosarcoma. Here, we review these cancer signaling pathways, including Notch, Wnt, Hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, and JAK/STAT, and their specific role in osteosarcoma. In addition, we highlight numerous natural compounds that have been documented to target these pathways effectively, including curcumin, diallyl trisulfide, resveratrol, apigenin, cyclopamine, and sulforaphane. We elucidate through references that these natural compounds can induce cancer signaling pathway manipulation and possibly facilitate new treatment modalities for osteosarcoma.

Background: The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment with liposomal preparation of siDCAMKL-1. In this report, we have utilized Nanoparticle (NP) technology to deliver DCAMKL-1 specific siRNA to knockdown potential key cancer regulators. In this study, mRNA/miRNA were analyzed using real-time RT-PCR and protein by western blot/immunohistochemistry. siDCAMKL-1 was encapsulated in Poly(lactide-co-glycolide)-based NPs (NP-siDCAMKL-1); Tumor xenografts were generated in nude mice, treated with NP-siDCAMKL-1 and DAPT (γ-secretase inhibitor) alone and in combination. To measurelet-7aandmiR-144expressionin vitro, HCT116 cells were transfected with plasmids encoding the firefly luciferase gene withlet-7aandmiR-144miRNA binding sites in the 3'UTR.Results: Administration of NP-siDCAMKL-1 into HCT116 xenografts resulted in tumor growth arrest, downregulation of proto-oncogene c-Myc and Notch-1 vialet-7aandmiR-144miRNA-dependent mechanisms, respectively. A corresponding reduction inlet-7aandmiR-144specific luciferase activity was observedin vitro. Moreover, an upregulation of EMT inhibitormiR-200aand downregulation of the EMT-associated transcription factors ZEB1, ZEB2, Snail and Slug were observedin vivo. Lastly, DAPT-mediated inhibition of Notch-1 resulted in HCT116 tumor growth arrest and down regulation of Notch-1 via amiR-144dependent mechanism.Conclusions: These findings demonstrate that nanoparticle-based delivery of siRNAs directed at critical targets such as DCAMKL-1 may provide a novel approach to treat cancer through the regulation of endogenous miRNAs.