Carcinogenic and Systemic Health Effects Associated with Arsenic Exposure - A Critical Review

Lee

Proc. Natl. Acad. Sci. U.S.A.

et al. 2010

285

244

Aberrant Hedgehog (Hh) pathway activation has been implicated in cancers of diverse tissues and organs, and the tumor growth-inhibiting effects of pathway antagonists in animal models have stimulated efforts to develop pathway antagonists for human therapeutic purposes. These efforts have focused largely on cyclopamine derivatives or other compounds that mimic cyclopamine action in binding to and antagonizing Smoothened, a membrane transductory component. We report here that arsenicals, in contrast, antagonize the Hh pathway by targeting Gli transcriptional effectors; in the short term, arsenic blocks Hh-induced ciliary accumulation of Gli2, the primary activator of Hh-dependent transcription, and with prolonged incubation arsenic reduces steady-state levels of Gli2. Arsenicals active in Hh pathway antagonism include arsenic trioxide (ATO), a curative agent in clinical use for acute promyelocytic leukemia (APL); in our studies, ATO inhibited growth of Hh pathway-driven medulloblastoma allografts derived from Ptch +/− p53 −/− mice within a range of serum levels comparable to those achieved in treatment of human APL. Arsenic thus could be tested rapidly as a therapeutic agent in malignant diseases associated with Hh pathway activation and could be particularly useful in such diseases that are inherently resistant or have acquired resistance to cyclopamine mimics.

Section: Discussionmentioning

confidence: 95%

Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector

Lee

Proc. Natl. Acad. Sci. U.S.A.

et al. 2010

285

244

“…In contrast, more recent data from animal models have shown the possibility of a strong bond with liver tumor formation [261][262][263][264][265][266][267][268] . Various carcinogenic mechanisms, genetic and epigenetic, have been proposed: DNA methylation, oxidative damage, genomic instability and reduction of programmed cell death [269][270][271][272][273][274] .…”

Section: Arsenicmentioning

confidence: 99%

Hepatocellular carcinoma and the risk of occupational exposure

Rapisarda

Loreto

Malaguarnera

et al. 2016

WJH

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The main risk factors for HCC are alcoholism, hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, obesity, type 2 diabetes, cirrhosis, aflatoxin, hemochromatosis, Wilson's disease and hemophilia. Occupational exposure to chemicals is another risk factor for HCC. Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent. This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem. Core tip: Hepatocellular carcinoma (HCC) is the fifth most common human cancer. This review summarizes current knowledge regarding the occupational risk factors of HCC. In particular, we underline not only the infective but also non-infective occupational risk exposure, including chemical agents and toxic metabolites which are a major cause of liver damage.

“…Various hypotheses have been proposed to explain the carcinogenicity of inorganic arsenic. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis [13,14]. The mode-of-action studies suggest that the arsenic might be acting as a cocarcinogen, a promoter or a progressor of carcinogensis [15].…”

Section: Mechanisms Of Arsenic Carcinogenesismentioning

confidence: 99%

Arsenic Carcinogenesis in the Skin

2006

SummaryChronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this