Cytotoxic effect of carbohydrate derivatives of digitoxigenin involves modulation of plasma membrane Ca²⁺‐ATPase

Abstract

Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na+/K+‐ATPase to induce anti‐neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi‐synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective and more effective analogs than the parent natural product. Therefore, the aim of this study was to assess the cytotoxic potential of novel digitoxigenin derivatives, digitoxigenin‐α‐L‐rhamno‐pyranoside (1) and digitoxigenin‐α‐L‐amiceto‐pyranoside (2), in cervical carcinoma cells (HeLa) and human diploid lung fibroblasts (Wi‐26‐VA4). In addition, we studied the anticancer mechanisms of action of these compounds by comparing its cytotoxic effects with the potential to modulate the activity of three P‐type ATPases; Na+/K+‐ATPase, sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA), and plasma membrane Ca2+‐ATPase (PMCA). Briefly, the results showed that compounds 1 and 2 were more cytotoxic and selectivity for HeLa tumor cells than the nontumor cells Wi‐26‐VA4. While the anticancer cytotoxicity in HeLa cells involves the modulation of Na+/K+‐ATPase, PMCA and SERCA, the modulation of these P‐type ATPases was completely absent in Wi‐26‐VA4 cells, which suggest the importance of their role in the cytotoxic effect of compounds 1 and 2 in HeLa cells. Furthermore, the compound 2 inhibited directly erythrocyte ghosts PMCA and both compounds were more cytotoxic than digitoxin in HeLa cells. These results provide a better understanding of the mode of action of the synthetic cardiac glycosides and highlights 1 and 2 as potential anticancer agents.

Effect of ouabain on calcium signaling in rodent brain: A systematic review of in vitro studies

“…From Ca 2+ -binding proteins inside cells to proteins that allow Ca 2+ fluxes across biological membranes, Ca 2+ concentrations are strictly controlled in cytoplasm and organelles like mitochondria, Golgi apparatus, endoplasmic reticulum and nucleus ( Brini et al, 2014 ). Ca 2+ Channels ( Koh et al, 2017 ), the high Ca 2+ affinity but low capacity plasma membrane Ca 2+ -ATPases and the low Ca 2+ affinity but high capacity Na + /Ca 2+ exchanger ( Blaustein et al, 2002 ), sarco/endoplasmic reticulum Ca 2+ -ATPases ( Valadares et al, 2021 ), and ryanodine and inositol 1,4,5-triphosphate (IP3) receptors ( McGarry and Williams, 1993 ), ( Panizza et al, 2019 ) are important for Ca 2+ handling and secondary targets for ouabain action.…”

Avaliação dos efeitos >i<in vivo>/i< e>i< in vitro>/i< da 21-p-hexoxi-m-metoxibenzilideno digoxina (BD-15) nas respostas induzidas por LPS.

“…Contudo, experimentos já feitos por nossos colaboradores mostraram que a BD-15 é pouco citotóxica inclusive em concentrações mais altas (VALADARES et al, 2021). Corroborando com os achados, a BD-15 não foi capaz de causar na BV-2 morte celular significativa em nenhuma das concentrações testadas.…”