Double-Edged Effects of Arsenic Compounds: Anticancer and Carcinogenic Effects

Abstract

Although arsenic is known to cause cancers of lung, skin and kidney, arsenic trioxide (As2O3) has been recently recognized as one of the most effective novel anticancer agent for the treatment of acute promyelocytic leukemia (APL). These paradoxical effects of arsenic may be dose-dependent, associated with its distinctive metabolism, or correlated with its direct or indirect effects on different cellular pathways which may result in altered cellular functions. The basic mechanism through which As2O3 induces molecular remission in APL patients include direct targeting of PML and retinoic acid receptor alpha fusion protein (PML-RARα) by arsenic resulting in oncoprotein degradation leading to partial differentiation. Many in vitro studies have also indicated that the anticancer properties of As2O3 against non-APL blood cancers predominantly occur through induction of apoptotic pathway. Especially, release of cytochrome c or activation of the caspase cascades and apoptosis-related proteins by arsenic is thought to occur by directly targeting mitochondria. The mechanisms and the selective target sites that have been usually associated with the cytotoxic effects of arsenicals are discussed here with reference to their contribution towards the anticancer properties of arsenic. In this review we have particularly explained the in vivo or in vitro arsenic toxicity based on arsenic metabolic pathway and its different metabolites. These multiple effects and different selective target sites for arsenic and its metabolites emphasize the need for better understanding of paradoxical effects of arsenic which may provide the appropriate use of this agent in the treatment of various malignancies.

Tobacco smoking induces metabolic reprogramming of renal cell carcinoma

“…Similarly, in the case of head and neck squamous cell carcinoma (HNSCC), while human papillomaviruses (HPV) are risk factors, HNSCCs (especially those involving the oropharynx) related to HPV have better prognosis (55). Moreover, Arsenic implicated in TS effects is recognized for its both oncogenic and chemotherapeutic activities (56).…”

“…The quality of raw, aligned, and counts data was assessed using fastQC (60) with an integration time of 0.15 seconds per isotope. A five-point calibration was generated for 75 As, 63 Cu, 111 Cd, 56 Fe, 60 Ni, 78 Se, 207 Pb, 34 S, 31 P, 55 Mn, 59 Co and 66 Zn with a spiked FBS sample in order to avoid column contamination by free metals, and to replicate the protein-matrix of the real samples. Supplemental Table 5D).…”

Distribution of Arsenic Resistance Genes in Prokaryotes

“…For example, DMMTAs(V) (dimethylmonothioarsinic Acid) is more toxic than DMA(V) (dimethylarsinic acid) ( Naranmandura et al, 2007 ). AS3MT is required for production of urinary methylated thioarsenates and oxythioarsenates in mice, indicating that As(III) methylation is a key step in formation of methylated thioarsenates ( Kanwal and Hua, 2013 ). Biomethylation of arsenite is usually attributed to the catalytic activity of ArsM/AS3MT.…”

Metabolism, toxicity and anticancer activities of arsenic compounds

“…One group reported that As 2 O 3 is metabolized into the methylated metabolites in the NB4 cell and argue that these intracellular methylated arsenic metabolites induce DNA hypomethylation and take part in the therapeutic effects of As 2 O 3 in APL. Thereby, we should have to consider the importance of arsenic metabolism and its metabolites for elucidating the probable role of different arsenic species (i.e., including precursor and its metabolites) in relation to toxicities as well as in therapeutic efficacies [34, 40, 62]. …”