АНТИКАНЦЕРОГЕННАЯ АКТИВНОСТЬ БРАССИНОСТЕРОИДОВ В ОПУХОЛЕВЫХ КЛЕТКАХ КАРЦИНОМЫ ПЕЧЕНИ

In this study, we first characterized the effect of natural brassinosteroids, 24-epibrassinolide (EBl) and 28-homocastasterone (HCS), and synthetic analogs, (22S,23S)-24-epibrassinolide and (22S,23S)-28-homocastastone, on the growth of the cancer cell line Hep G2 (hepatocellular carcinoma), as well as on the catalytic activity of cytochrome P450, which participates in the metabolism of most procarcinogens. All four compounds at high concentrations suppressed the proliferation of the test cell line. It is also interesting that at low concentrations, 24-EBl, (22S,23S)-24-EBl and (22S,23S)28-HCS activated significantly the Hep G2 cell growth. All studied brassinosteroids, except for 28-HCS, inhibited the activity of CYP1A1 and CYP1B1. The effect depended on the structure of the side chain and was more pronounced in the case of the SS orientation of the hydroxyl groups at the positions C22 and C23 ((22S,23S)-28-homocastasterone). The results of this work suggest that the studied brassinosteroids (especially (22S,23S)-28-homocastasterone) can be used to create effective drugs for tumor prevention and treatment.Впервые охарактеризовано влияние природных брассиностероидов 24-эпибрассинолида (24-ЭБ) и 28-гомокастастерона (28-ГКС), а также синтетических аналогов (22S,23S)-24-эпибрассинолида и (22S,23S)-28-гомокастастерона на пролиферацию активности в раковой клеточной линии Hep G2 (карцинома печени), а также на каталитическую активность цитохрома P450, который участвует в метаболизме большинства проканцерогенов. Все четыре соединения при высоких концентрациях были активными в подавлении клеточной пролиферации исследуемой линии. Интересным является и тот факт, что при низких концентрациях 24-ЭБ, (22S,23S)-24-ЭБ и (22S,23S)-28-ГКС достоверно активировали рост клеток Hep G2. Все исследуемые брассиностероиды ингибировали активность CYP1A1 и CYP1B1, за исключением 28-ГКС. Оказываемый эффект зависел от структуры боковой цепи и был более выражен в случае SSориентации гидроксильных групп в положении C22 и С23 ((22S,23S)-28-гомокастастерон). Полученные результаты указывают на возможность использования исследуемых брассиностероидов (в наибольшей степени (22S,23S)-28-ГКС) для создания более эффективных препаратов для профилактики и лечения опухолевых заболеваний.

Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate

Widespread pathologies such as atherosclerosis, metabolic syndrome and cancer are associated with dysregulation of sterol biosynthesis and metabolism. Cholesterol modulates the signaling pathways of neoplastic transformation and tumor progression. Lanosterol 14-alpha demethylase (cytochrome P450(51), CYP51A1) catalyzes one of the key steps in cholesterol biosynthesis. The fairly low somatic mutation frequency of CYP51A1, its druggability, as well as the possibility of interfering with cholesterol metabolism in cancer cells collectively suggest the clinical importance of CYP51A1. Here, we show that the natural flavonoid, luteolin 7,3′-disulfate, inhibits CYP51A1 activity. We also screened baicalein and luteolin, known to have antitumor activities and low toxicity, for their ability to interact with CYP51A1. The Kd values were estimated using both a surface plasmon resonance optical biosensor and spectral titration assays. Unexpectedly, in the enzymatic activity assays, only the water-soluble form of luteolin—luteolin 7,3′-disulfate—showed the ability to potently inhibit CYP51A1. Based on molecular docking, luteolin 7,3′-disulfate binding suggests blocking of the substrate access channel. However, an alternative site on the proximal surface where the redox partner binds cannot be excluded. Overall, flavonoids have the potential to inhibit the activity of human CYP51A1 and should be further explored for their cholesterol-lowering and anti-cancer activity

pH-Sensitive fluorescent sensor for Fe(III) and Cu(II) ions based on rhodamine B acylhydrazone: Sensing mechanism and bioimaging in living cells

Spirocyclic rhodamine derivatives have great potential to be used as fluorescent sensors. Rho- damine B hydrazide (RBH) and its derivatives have been employed to detect various analytes. The interactions of a sensor with an analyte might result in the protonation or hydrolysis of the sensor. Understanding these processes is useful for developing new sensors with improved characteristics. In this work, the performance of rhodamine B acylhydrazone (RBA) as a sensor for Fe3+ and Cu2+ ions is evaluated. In the presence of these ions, RBA undergoes protonation and the spirolactam ring opening. The ring opening renders the dye colored and fluorescent. RBA is then hydrolyzed to RBH leading to the decay of the absorbance in the visible range. The protonation and hydrolysis of RBA are acid-catalyzed, and metal ions contribute to these processes by lowering pH. Metal ions, unlike hydrogen ions, catalyze the transformation of RBH into rhodamine B and a phenanthrenone derivative. These products exhibit emission bands in the visible and near-infrared ranges, respectively. The obtained results can be applied to a variety of sensors based on rhodamines and Schiff bases. RBA can be employed for bioimaging. RBA quickly penetrates into cells, localizes in the organelles with acidic pH, probably in lysosomes, persists there for a long time, and gives bright fluorescence in the visible range. Cell incubation with Cu2+ ions produces fluorescence in the near-infrared range. RBA can be used as a multifunctional fluorescent biosensor to visualize cell compartments with acidic pH and detect Cu2+ ions in living cells.publishe