Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

Overexpression of miR-7-1 increases efficacy of green tea polyphenols for induction of apoptosis in human malignant neuroblastoma SH-SY5Y and SK-N-DZ cells.

Neuroblastoma is an extracranial solid tumor that usually occurs in infants and children. Malignant neuroblastomas remain mostly refractory to currently available chemotherapeutic agents. So, new therapeutic agents and their molecular mechanisms for induction of cell death must be explored for successful treatment of human malignant neuroblastomas. Two polyphenolic compounds, which are abundant in green tea, are (-)-epigallocatechin (EGC) and (-)-epigallocatechin-3-gallate (EGCG) that possess impressive anti-cancer properties. It is not known yet whether EGC and EGCG can modulate the levels of expression of specific microRNAs (miRs) for induction of apoptosis in human malignant neuroblastomas. In this investigation, we revealed that treatment with EGC or EGCG caused induction of apoptosis with significant changes in expression of specific oncogenic miRs (OGmiRs) and tumor suppressor miRs (TSmiRs) in human malignant neuroblastoma SH-SY5Y and SK-N-DZ cell lines. Treatment of both cell lines with either 50 µM EGC or 50 µM EGCG decreased expression of the OGmiRs (miR-92, miR-93, and miR-106b) and increased expression of the TSmiRs (miR-7-1, miR-34a, and miR-99a) leading to induction of extrinsic and intrinsic pathways of apoptosis. Our data also demonstrated that overexpression of miR-93 decreased efficacy while overexpression of miR-7-1 increased efficacy of the green tea polyphenols for induction of apoptosis in both cell lines. In conclusion, our current investigation clearly indicates that overexpression of miR-7-1 can highly potentiate efficacy of EGCG for induction of apoptosis in human malignant neuroblastoma cells.

Molecular characterization of genome segment 2 encoding RNA dependent RNA polymerase of Antheraea mylitta cytoplasmic polyhedrosis virus.

Genome segment 2 (S2) from Antheraea mylitta cypovirus (AmCPV) was converted into cDNA, cloned and sequenced. S2 consisted of 3798 nucleotides with a long ORF encoding a 1116 amino acid long protein (123 kDa). BLAST and phylogenetic analysis showed 29% sequence identity and close relatedness of AmCPV S2 with RNA dependent RNA polymerase (RdRp) of other insect cypoviruses, suggesting a common origin of all insect cypoviruses. The ORF of S2 was expressed as 123 kDa soluble His-tagged fusion protein in insect cells via baculovirus recombinants which exhibited RdRp activity in an in vitro RNA polymerase assay without any intrinsic terminal transferase activity. Maximum activity was observed at 37 degrees C at pH 6.0 in the presence of 3 mM MgCl(2). Site directed mutagenesis confirmed the importance of the conserved GDD motif. This is the first report of functional characterization of a cypoviral RdRp which may lead to the development of anti-viral agents.