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Long-Term Toxicity and Regulations for Bioactive-Loaded Nanomedicines
Published in Mahfoozur Rahman, Sarwar Beg, Mazin A. Zamzami, Hani Choudhry, Aftab Ahmad, Khalid S. Alharbi, Biomarkers as Targeted Herbal Drug Discovery, 2022
Iqbal Ahmad, Sobiya Zafar, Shakeeb Ahmad, Suma Saad, S. M. Kawish, Sanjay Agarwal, Farhan Jalees Ahmad
Resveratrol, a compound found in grapes, mulberries, and peanuts, has demonstrated antioxidant, anti-inflammatory, antiproliferative, and proapoptotic properties. The dose-limiting toxicity studies were carried out for determining any potential toxicity associated with resveratrol. A dose of 3000 mg/Kg body weight (BW) for 28 days caused nephrotoxicity in rats, evident with an enhanced level of serum BUN and creatinine levels, increased kidney weights, and gross renal pathology changes, also caused anemia due to reduced erythropoietin synthesis in the kidneys. The dose of 1000 or 300 mg/kg BW/ day did not result in nephrotoxic findings (Crowell et al., 2004). Some active constituents of cruciferous vegetables can also produce toxic effects. Akagi et al. reported that the oral administration of 0.1% phenethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC) in the rat diet-induced continuous urinary epithelial cell proliferation and simple and papillary or nodular (PN) hyperplasias, resulting in bladder carcinogenesis in rats (Akagi et al., 2003). The intracellular ROS generated from the N=S group of the isothiocyanates (ITCs) produces the cytotoxic and genotoxic effects and subsequent oxidative DNA damage (Russo et al., 2010).
Nutrition and the Risk of Common Forms of Cancer
Published in David Heber, Zhaoping Li, Primary Care Nutrition, 2017
Glucosinolates and their derivatives, which include isothiocyanates, phenylethyl isothiocyanate, di-indolyl methane, and indole-3-carbinol, may modulate many relevant processes, such as the induction of metabolic enzymes in the liver; inhibition of inflammatory processes; modulation of cancer signaling pathways, including cellular proliferation; angiogenesis; the epithelial–mesenchymal transition; cancer stem cell self-renewal; and suppression of diverse oncogenic signaling pathways, including nuclear factor κB (NF-κB), hormone receptor, and the signal transducer and activator of transcription (Mukherjee et al. 2008; H. Wang et al. 2012; X. Wang et al. 2012). Glucosinolate derivatives have the potential to modulate epigenetic alterations, such as DNA methylation, histone modifications, noncoding microRNAs (miRNAs), regulation of polycomb group proteins, and epigenetic cofactor modifiers, all of which may contribute to carcinogenesis (Link et al. 2010; H. Wang et al. 2012).
Plant-Based Compounds as Alternative Adjuvant Therapy for Multidrug-Resistant Cancer
Published in Parimelazhagan Thangaraj, Phytomedicine, 2020
E. C. Aniogo, Blassan P. George, Heidi Abrahamse
The biological activity of carotenoids as reported by previous studies indicated that they exhibit anticancer properties through cell cycle arrest, growth factor inhibition transduction, stimulation of anti-oncogene proteins, and apoptotic mechanism induction (Garattini et al. 2007; Yu et al. 2011). The carotenes, xanthophylls, and retinoids class of carotenoids have a high affinity to a P-gp transporter and are thus used as a competitive inhibitor for the transporter (Gyemant et al. 2006). This was apparent in the findings of Eid et al. (2012) using MDR-resistant colon and leukemia cells. Eid and colleagues confirmed that the five carotenoids (β-carotene, crocin, retinoic acid, canthaxanthin, and fucoxanthin) studied competitively inhibit the P-gp activity in both the colon and leukemic cell line. These compounds increased drug accumulation and efficacy in the resistant cells and reversed the MDR effect of the chemotherapeutic drugs in a synergistic fashion. Likewise, many naturally occurring isothiocyanates display anticarcinogenic activity because they reduce the activation of carcinogens and increase their detoxification (Wu et al. 2009). Recent studies show that phenethyl isothiocyanate, a natural compound found in cruciferous vegetables, can suppress cancer stem cell properties in vitro and in a xenograft model. Yun and colleagues (2017) revealed that ABCG2 as well as pluripotent-associated transcription factors in epithelial cellular adhesion molecule (EpCAM)-positive NCCIT, a pluripotent stem cell line established by Shinichi Teshima (National Cancer Institute, Tokyo, Japan), human embryonic carcinoma cells, such as octamer-binding transcription (Oct4), sex-determining region Y-box (Sox-2), and NANOG were downregulated by phenethyl isothiocyanate. Previous studies have reported that cancer stem cells exhibit drug resistance through the expression of ABCG2, which closely correlates with the expression of pluripotency factors. Thus, isocyanate compounds are useful in targeting cancer stem cells, which are a source of tumor initiating cells and contribute in drug resistance.
Susceptibility to the acute toxicity of acrylonitrile in streptozotocin-induced diabetic rats: protective effect of phenethyl isothiocyanate, a phytochemical CYP2E1 inhibitor
Published in Drug and Chemical Toxicology, 2021
Fang Li, Ying Dong, Rongzhu Lu, Bobo Yang, Suhua Wang, Guangwei Xing, Yuanyue Jiang
Phenethyl isothiocyanate (PEITC), a naturally occurring compound characterized by its N=C=S functional group, is derived from the hydrolysis of its glucosinolate precursor gluconasturtiin in widely consumed cruciferous vegetables, such as broccoli, cabbage, and watercress. PEITC has attracted attention for its ability to inactivate CYP2E1 (Yoshigae et al. 2013). Furthermore, PEITC, a potent Nrf2 activator, has also been shown to enhance detoxification via phase II enzymes, such as quinone reductase and glutathione S-transferase (GST) (Cheung et al. 2009), and promote an increase in glutathione (GSH). GST represents a superfamily of enzymes that are expressed in different isoforms encoded by a variety of genes (Franco et al. 2007, Dalmizrak et al. 2016). These multifunctional enzymes are involved in the elimination of reactive oxygen species (ROS) contributing to detoxification and cell protection via conversion of many endogenous and exogenous electrophilic compounds to less reactive metabolites. GSH, a non-enzymatic free radical scavenger, plays a key role in antioxidative processes and its depletion results in a low scavenging capacity for ROS. GSH participates in the enzymatic reduction of membrane hydroperoxy-phospholipids and prevents the formation of secondary alkoxyl radicals when organic peroxides are homolyzed (Franco et al. 2007).
Characterisation of naturally occurring isothiocyanates as glutathione reductase inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Xia Li, Maowei Ni, Xiaoling Xu, Wei Chen
Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) (Figure 1), allyl isothiocyanate (AITC) and sulforaphane (SFN) are the most common ITCs which have been shown to have anticancer, autophagy and apoptosis-inducing effects4–8. ITCs exert bioactivities mainly by interacting with thiol and amine groups in peptides and proteins3. ATP synthase (Complex I), cytochrome c oxidase (Complex IV) and thioredoxin-dependent peroxide reductase have been identified as potential ITC targets, the inhibition of which may lead to reactive oxygen species (ROS) accumulation9. Several mechanisms have been proposed for ITCs, including the generation of ROS, depletion of glutathione and initiation of cell cycle arrest1,9–12. However, the role of ITCs in regulation of intracellular ROS and oxidative stress is not fully understood.
Precision medicine for TP53-mutated acute myeloid leukemia
Published in Expert Review of Precision Medicine and Drug Development, 2019
Marte Karen Brattås, Håkon Reikvam, Tor Henrik Anderson Tvedt, Øystein Bruserud
Phenethyl isothiocyanate (PEITC) targets the R175H TP53 mutation and has been investigated for the AML cell lines U937 and HL-60, the T-cell leukemia line Jurkat and primary human AML cells [48]. PEITC had proapoptotic effects with activation of caspases 3, 8 and 9; increased cleavage/degradation of poly ADP ribose polymerase, caspase-independent downregulation of Mcl-1 (induced myeloid leukemia cell differentiation protein), inactivation of Akt and activation of Jun N-terminal kinase (JNK). The proapoptotic effect of PEITC was further enhanced by PI3K/Akt inhibition, and activation of Akt antagonized the proapoptotic effects. PEITC-induced apoptosis was also attenuated by inhibition of the JNK pathway. Finally, PEITC-inhibited tumor growth and induced apoptosis in a U937 xenograft model, and this effect was also associated with inactivation of Akt, activation of JNK and downregulation of Mcl-1.