A growing number of studies indicate that breast cancer initiation is related to abnormal estrogen oxidation to form an excess of estrogen-3,4-quinones, which react with DNA to form depurinating adducts and induce mutations. This mechanism is often called estrogen genotoxicity. 4-Catechol estrogens, precursors of the estrogen-3,4-quinones, were previously shown to account for most of the transforming and tumorigenic activity. We examined whether estrogen-induced transformation can be reduced by inhibiting the oxidation of a 4-catechol estrogen to its quinone. We demonstrate that E6 cells (a normal mouse epithelial cell line) can be transformed by a single treatment with a catechol estrogen or its quinone. The transforming activities of 4-hydroxyestradiol and estradiol-3,4-quinone were comparable. N-Acetylcysteine, a common antioxidant, inhibited the oxidation of 4-hydroxyestradiol to the quinone and consequent formation of DNA adducts. It also drastically reduced estrogen-induced transformation of E6 cells. These results strongly implicate estrogen genotoxicity in mammary cell transformation. Since N-acetylcysteine is well tolerated in clinical studies, it may be a promising candidate for breast cancer prevention.
Polycyclic aromatic hydrocarbons (PAH) form stable and depurinating DNA adducts in mouse skin to induce preneoplastic mutations. Some mutations transform cells, which then clonally expand to establish tumors. Strong clues about the mutagenic mechanism can be obtained if the PAH-DNA adducts can be correlated with both preneoplastic and tumor mutations. To this end, we studied mutagenesis in PAH-treated early preneoplastic skin (1 day after exposure) and in the induced papillomas in SENCAR mice. Papillomas were studied by PCR amplification of the H-ras gene and sequencing. For benzo [a]pyrene (BP), 7, anthracene (DMBA) and dibenzo [a,l]pyrene (DB[a,l]P), the codon 13 (GGC to GTC) and codon 61 (CAA to CTA) mutations in papillomas corresponded to the relative levels of Gua and Adedepurinating adducts, despite BP and BPDHD forming significant amounts of stable DNA adducts. Such a relationship was expected for DMBA and DB[a,l]P, as they formed primarily depurinating adducts. These results suggest that depurinating adducts play a major role in forming the tumorigenic mutations. To validate this correlation, preneoplastic skin mutations were studied by cloning Hras PCR products and sequencing individual clones. DMBA-and DB[a,l]P-treated skin showed primarily A.T to G.C mutations, which correlated with the high ratio of the Ade/Gua-depurinating adducts. Incubation of skin DNA with T.G-DNA glycosylase eliminated most of these A.T to G.C mutations, indicating that they existed as G.T heteroduplexes, as would be expected if they were formed by errors in the repair of abasic sites generated by the depurinating adducts. BP and its metabolites induced mainly G.C to T.A mutations in preneoplastic skin. However, PCR over unrepaired anti-BPDE-N 2 dG adducts can generate similar mutations as artifacts of the study protocol, making it difficult to establish an adduct-mutation correlation for determining which BP-DNA adducts induce the early preneoplastic mutations. In conclusion, this study suggests that depurinating adducts play a major role in PAH mutagenesis.
Nanoparticles (NPs) are elements derived from a cluster of atoms with one or more dimensions in the nanometer scale in the range of 1–100 nm. The bio nanofabrication of metallic NPs is now an important dynamic area of research, with major significance in applied research. Biogenic synthesis of NPs is more desirable than physical and chemical synthesis due to its eco-friendliness, non-toxicity, lower energy consumption, and multifunctional nature. Plants outperform microorganisms as reducing agents as they contain large secondary biomolecules that accelerate the reduction and stability of the NPs. The produced NPs can then be studied spectroscopically (UV-Visible, XRD, Raman, IR, etc.) and microscopically (SEM, TEM, AFM, etc.). The biological reduction of a metallic ion or its oxide to a nanoparticle is quick, simple, and may be scaled up at room temperature and pressure. The rise in multi-drug resistant (MDR) microbes due to the immoderate use of antibiotics in non-infected patients is a major cause of morbidity and mortality in humans. The contemporary development of a new class of antibiotics with different mechanisms of action to kill microbes is crucial. Metals and their oxides are extremely toxic to microbes at unprecedentedly low concentrations. In addition, prevailing infections in plants and animals are raising significant concerns across the globe. NPs’ wide range of bioactivity makes them ideal antimicrobial agents in agricultural and medical fields. The present review outlines the synthesis of metallic NPs from botanicals, which enables the metals to be in a stabilized form even after ionization. It also presents a valuable database on the biofunctionalization of synthesized NPs for further drug development.
Mitochondria are a major intracellular organelle for drug targeting due to its functional roles in cellular metabolism and cell signaling for proliferation and cell death. Mitochondria-targeted treatment strategy could be promising to improve the therapeutic efficacy of cancer while minimizing the adverse side effects. Over the last decades, several studies have explored and focused on mitochondrial functions, which has led to the emergence of mitochondria-specific therapies. Molecules in the mitochondria are considered to be prime targets, and a wide range of molecular strategies have been designed for targeting mitochondria compared with that of the cytosol. In this review, we focused on the molecular mechanisms of mitochondria-specific ligand targeting and selective drug action strategies for targeting mitochondria, including those premised on mitochondrial targeting of signal peptides (MTS), cell-penetrating peptides (CPPs), and use of lipophilic cations. Furthermore, most research has concentrated on specific conjugation of ligands to therapeutic molecules to enhance their effectiveness. There are several variations for the ideal design and development for mitochondrial-targeted drugs, such as selecting a suitable ligand and linker targets. However, some challenges related to drug solubility and selectivity could be resolved using the nanocarrier system. Nanoparticles yield excellent advantages for targeting and transmitting therapeutic drugs, and they offer elegant platforms for mitochondria-specific drug delivery. We explain many of the advanced and proven strategies for multifunctional mitochondria-specific targets, which should contribute to achieving better anticancer therapies in a promising future.
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