Pleiotrophic effects of natural products in ROS-induced carcinogenesis: the role of plant-derived natural products in oral cancer chemoprevention.

Cancer is a multistage process where each stage involves different molecular, biochemical and cellular events all of which, however, contribute to malignant transformation. Over the last years, substantial scientific evidence has promoted the hypothesis that ROS-induced cellular damage underlies key steps during development of the malignant phenotype including evasion of apoptosis, limitless proliferation, angiogenesis, tissue invasion and metastasis, etc. On the other hand, natural products hold great promise as anti-cancer compounds in preventing against carcinogenesis both in vitro and in vivo. Throughout this article, we aim to review the evidence as to how some of these natural products exert their chemopreventive effects in human carcinogenesis. For this reason, we have placed particular emphasis on oral cancer where significant efforts have been made in alternative therapeutic strategies such as the use of plant-derived natural products. This is of paramount importance given the disease's high morbidity and mortality rates across the world and specifically in the geographic regions of India and South-East Asia where its incidence is increasing.

Reactive oxygen species (ROS)--induced genetic and epigenetic alterations in human carcinogenesis.

Cancer is a multistage and complex process characterized by molecular alterations that underlie all three phases of its development: (i) initiation, (ii) promotion and (iii) progression. Some of these molecular events include alterations in gene expression that are regulated by both genetic and epigenetic mechanisms. On the other hand, "oxidative stress" implies a cellular state where ROS production exceeds the cell's ability to metabolize them resulting in excessive accumulation of ROS that overwhelms cellular defenses. Such state has been shown to regulate both genetic and epigenetic cascades underlying altered gene expression in human disease including cancer. Throughout this manuscript, we review the current state of knowledge on the role of ROS-induced oxidative stress in altering the genetic and epigenetic involvement during human carcinogenesis.

Direct evidence for functional smooth muscle myosin II in the 10S self-inhibited monomeric conformation in airway smooth muscle cells.

The 10S self-inhibited monomeric conformation of myosin II has been characterized extensively in vitro. Based upon its structural and functional characteristics, it has been proposed to be an assembly-competent myosin pool in equilibrium with filaments in cells. It is known that myosin filaments can assemble and disassemble in nonmuscle cells, and in some smooth muscle cells, but whether or not the disassembled pool contains functional 10S myosin has not been determined. Here we address this question using human airway smooth muscle cells (hASMCs). Using two antibodies against different epitopes on smooth muscle myosin II (SMM), two distinct pools of SMM, diffuse, and stress-fiber-associated, were visualized by immunocytochemical staining. The two SMM pools were functional in that they could be interconverted in two ways: (i) by exposure to 10S- versus filament-promoting buffer conditions, and (ii) by exposure to a peptide that shifts the filament-10S equilibrium toward filaments in vitro by a known mechanism that requires the presence of the 10S conformation. The effect of the peptide was not due to a trivial increase in SMM phosphorylation, and its specificity was demonstrated by use of a scrambled peptide, which had no effect. Based upon these data, we conclude that hASMCs contain a significant pool of functional SMM in the 10S conformation that can assemble into filaments upon changing cellular conditions. This study provides unique direct evidence for the presence of a significant pool of functional myosin in the 10S conformation in cells.

The role of epigenetics in environmental and occupational carcinogenesis.

Over the last few years there has been an increasing effort in identifying environmental and occupational carcinogenic agents and linking them to the incidence of a variety of human cancers. The carcinogenic process itself is multistage and rather complex involving several different mechanisms by which various carcinogenic agents exert their effect. Amongst them are epigenetic mechanisms often involving silencing of tumor suppressor genes and/or activation of proto-oncogenes, respectively. These alterations in gene expression are considered critical during carcinogenesis and have been observed in many environmental- and occupational-induced human cancers. Some of the underlying mechanisms proposed to account for such differential gene expression include alterations in DNA methylation and/or histone modifications. Throughout this article, we aim to provide a current account of our understanding on how the epigenetic pathway is involved in contributing to an altered gene expression profile during human carcinogenesis that ultimately will allow us for better cancer diagnostics and therapeutic strategies.

The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development.

Although we have greatly benefited from the use of traditional epidemiological approaches in linking environmental exposure to human disease, we are still lacking knowledge in to how such exposure participates in disease development. However, molecular epidemiological studies have provided us with evidence linking oxidative stress with the pathogenesis of human disease and in particular carcinogenesis. To this end, oxidative stress-based biomarkers have proved to be essential in revealing how oxidative stress may be mediating toxicity induced by many known carcinogenic environmental agents. Therefore, throughout this review article, we aim to address the current state of oxidative stress-based biomarker development with major emphasis pertaining to biomarkers of DNA, lipid and protein oxidation.

Viral-induced human carcinogenesis: an oxidative stress perspective.

Oncogenic transformation occurs via many different mechanisms. Alterations in the expression of certain key genes (oncogenes and/or tumor suppressor genes) contribute to the development of the tumorigenic state of uncontrolled cell proliferation. Tumor viruses' studies have contributed over the last 2 decades significantly in cancer etiology, first by providing valuable information on the mechanisms and dissection of cell signaling and growth control pathways and second by being causative agents of human neoplasia. Viruses contribute to the development of the neoplastic state through many mechanisms: inactivation of tumor suppressor genes, hyperstimulation of cellular proto-oncogene transcription, or by viral protein interference with the cellular transcription, signal transduction, DNA repair and apoptosis pathways and induction of chronic oxidative stress. On the other hand, only recently research has provided evidence of the epigenetic pathway involvement and especially the DNA methylation machinery. To this end, both hypomethylation-induced oncogenic activation and/or hypermethylation-induced tumor suppressor gene silencing are linked with viral-induced carcinogenesis. In this review, we discuss the current status of knowledge on viral-associated carcinogenesis with emphasis on the mechanisms of oxidative stress and DNA damage induction in humans by viruses as well as implications in cancer treatment.

BRCA1 involvement in toxicological responses and human cancer etiology.

Breast cancer associated gene 1 (BRCA1) gene is located on the long (q) arm of chromosome 17 at position 21. In the nucleus of many types of normal cells, BRCA1 protein interacts with several other proteins to mend strand breaks in DNA. It is generally considered a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. Exposure to various environmental and genetic factors can induce a severe impact on life span and lead to neoplastic transformation. BRCA1 through its participation in the control mechanisms of cell growth and DNA repair is lately considered as an important component of mammary homeostasis. In this review we summarize the different cellular functions and roles of this gene, the experimental evidence for its linkage to carcinogenesis and recent evidence tying BRCA1 to environmentally induced toxic-stress responses. Finally, we discuss the new insights in the exploitation of BRCA1 defects for the development of new therapeutic strategies in cancer treatment and clinical applications.