Lehka L. Functional interconnections between structure and antitumor activity of antibiotics of landomycin family

Aim of the work: Comparison of structural and functional interactions in the antitumor activity of various members of antibiotics of landomycin family in vitro, as well as the investigation of signaling mechanisms of cell death under their action and the elucidation of the influence of landomycins on tumor cells in vivo.Object of the research: apoptosis induced by landomycins in tumor cells. Methods: Cell-biological, molecular biological and biochemical. It was shown that the cytotoxic activity of the investigated compounds was directly proportional to the length of their oligosaccharide chain. The values of the IC50 of landomycins without 11-OH group in the aglycone decreased significantly (2-5 times) compared to their counterparts in which it was present. Studied compounds were able to overcome multidrug resistance of tumor cells to chemotherapy caused by overexpression of ABC transporters (P-gp, MRP1, BCRP, LRP1), overexpression of MEK1/2 kinase or knockout of genes, which proteins are involved in cell cycle regulation and apoptosis. The proapoptic action of landomycins is accompanied by the early (during the first hour) generation of reactive oxygen species (hydrogen peroxide). Dehydrogenase NQO1 plays an important role in the production of hydrogen peroxide by tumor cells under landomycins action. The intracellular molecular target of landomycins is effector caspase 7, which is involved in apoptosis, an early (1 hour) activation of it occurs before the activation of other effector and initiator caspases. Landomycin A, the most active member of the family of landomycins, significantly inhibits the growth of lymphoma NK/Ly and melanoma B16F10 in tumor-bearing mice, greatly improving their physiological state and prolonging their life span.