Background/Aim: We previously have described the "3+1" tumors cure approach consisting of individual time schedule of cyclophosphamide and dsDNA preparation administrations. The aim of the study was to adapt the "3+1" approach based on eradication of cancer stem cells to the model of murine ascitic cyclophosphamide-resistant lymphosarcoma (RLS). Materials and Methods: Adaptation of the "3+1" approach includes the identification of the timing to disrupt the tumorigenic potential of a certain tumor. Results: The proposed therapeutic scheme allowed complete reduction of primary RLS ascites in experimental animals. However, reduction of primary ascites due to the complementary action of cyclophosphamide and dsDNA was inevitably followed by the development of a secondary one, most likely arising from a solid carcinomatous formation in the peritoneal wall. Conclusion: The "3+1" approach resulted in the elimination of cancer stem cells, and, as a consequence, in the complete reduction of RLS ascites.Malignant neoplasms rank second in the world after cardiovascular disorders in overall mortality rates. Recent studies indicate a much higher complexity of the disease than previously thought. The main characteristic of this complexity determining the unpredictable response of neoplasms to a variety of therapeutic procedures and the difficulties in their cure is the heterogeneity of malignant cells that include a subpopulation of almost "indestructible" cells, which possess an incredible survival and proliferative potency, and is designated as tumor-initiating stem cells or cancer stem cells (CSCs) (1, 2).The main hallmarks of cancer stem cells are their capabilities of (1) self-renewal in through unlimited replicative cycles, (2) producing a progeny of committed cells with high proliferative activity, but incapable of inducing a new tumor, and (3) retaining a potency to induce new tumors with similar histological properties in a series of transplantations (3). CSCs possess a number of features allowing their dominance in co-existence with organism: self-sufficiency in proliferative stimuli (4), reduced sensitivity to anti-proliferative ones (5), immortalization (6, 7), dedifferentiation (8), genomic instability (9), increased efflux and metabolism of xenobiotics (10, 11), reversed "Warburg effect" (12, 13), suppression of pro-apoptotic signals ( 14), as well as stimulation of pathways causing apoptosis evasion (15). Another essential for disease development property of CSCs is their migratory capacity, allowing exit into the bloodstream, and formation of new growth foci in distant organs (16)(17)(18)(19)(20). Thus, the aforementioned properties of CSCs are such that they create 795
The Drosophila Nonspecific Lethal (NSL) complex is a major transcriptional regulator of housekeeping genes. It contains at least seven subunits that are conserved in the human KANSL complex: Nsl1/Wah (KANSL1), Dgt1/Nsl2 (KANSL2), Rcd1/Nsl3 (KANSL3), Rcd5 (MCRS1), MBD-R2 (PHF20), Wds (WDR5) and Mof (MOF/KAT8). Previous studies have shown that Dgt1, Rcd1 and Rcd5 are implicated in centrosome maintenance. Here, we analyzed the mitotic phenotypes caused by RNAi-mediated depletion of Rcd1, Rcd5, MBD-R2 or Wds in greater detail. Depletion of any of these proteins in Drosophila S2 cells led to defects in chromosome segregation. Consistent with these findings, Rcd1, Rcd5 and MBD-R2 RNAi cells showed reduced levels of both Cid/CENP-A and the kinetochore component Ndc80. In addition, RNAi against any of the four genes negatively affected centriole duplication. In Wds-depleted cells, the mitotic phenotypes were similar but milder than those observed in Rcd1-, Rcd5- or MBD-R2-deficient cells. RT-qPCR experiments and interrogation of published datasets revealed that transcription of many genes encoding centromere/kinetochore proteins (e.g., cid, Mis12 and Nnf1b), or involved in centriole duplication (e.g., Sas-6, Sas-4 and asl) is substantially reduced in Rcd1, Rcd5 and MBD-R2 RNAi cells, and to a lesser extent in wds RNAi cells. During mitosis, both Rcd1-GFP and Rcd5-GFP accumulate at the centrosomes and the telophase midbody, MBD-R2-GFP is enriched only at the chromosomes, while Wds-GFP accumulates at the centrosomes, the kinetochores, the midbody, and on a specific chromosome region. Collectively, our results suggest that the mitotic phenotypes caused by Rcd1, Rcd5, MBD-R2 or Wds depletion are primarily due to reduced transcription of genes involved in kinetochore assembly and centriole duplication. The differences in the subcellular localizations of the NSL components may reflect direct mitotic functions that are difficult to detect at the phenotypic level, because they are masked by the transcription-dependent deficiency of kinetochore and centriolar proteins.
The neurodegeneration is one of the features of aging and age-related disorders. Yet, only several antiaging interventions are known to affect the processes of neurodegeneration. Here we show that overexpression of the pro-longevity gene D-GADD45 in Drosophila neurons leads to a postponed manifestation of histological and ultrastructural features of age-dependent neurodegeneration, such as decrease in the packing density of neurons, increasing the degree of neuron cytoplasmic vacuolization, and morphological defects of mitochondrial cristae. Thus, the previously observed (Plyusnina, Biogerontology 12: 211-226, 2011) life extending effect of D-GADD45 overexpression in the nervous system is associated with delayed neurodegeneration.
Cumulative evidence obtained in this series of studies has guided the logic behind the development of a novel composite dsDNA-based preparation whose therapeutic application according to the specific regimen completely cures the mice engrafted with otherwise lethal Krebs-2 ascites. The likely mechanism involves elimination of TAMRA+ tumor-inducing stem cells (TISCs) from Krebs-2 tumors. We performed quantitative analysis of TISC dynamics in Krebs-2 Совокупность всех данных, полученных в работах настоящего цикла исследований, определила основную логику создания нового сложнокомпозиционного препарата на основе двуцепо-чечной ДНК, применение которого в рамках нового терапевтиче-ского режима привело к полному вылечиванию мышей от асцита Кребс-2. Рассматривается предполагаемый механизм разрушения туморогенного начала опухоли Кребс-2, который заключается в элиминации из опухоли TAMRA+ стволовых инициирующих раковых клеток (СИРК). Проведен анализ изменения количества СИРК Кребс-2 в нативном асците и асците после обработки цито-статиком циклофосфаном (ЦФ). В нативном асците количество СИРК осциллирует на определенном уровне. После обработки циклофосфаном их количество относительно оставшихся после масштабного апоптоза коммитированных раковых клеток увели -чивается по сравнению с исходным, что предполагает понижен ную чувствительность СИРК к действию циклофосфана. Тем не менее произошедшая в результате проведенных обработок синхрони-зация СИРК в чувствительной фазе клеточного цикла делает их доступными для действия терапевтических агентов. Охарактери-зо ван режим синергичного воздействия циклофосфана и препа-рата ДНК на развивающуюся асцитную опухоль Кребс-2, приводя-щего к полному вылечиванию 50 % экспериментальных живот ных. Этот режим включает трехкратные инъекции цитостатика цикло-фосфана в конечные точки каждого из трех последователь ных репаративных циклов, дополненные инъекциями препарата двуцепочечной ДНК через 18 ч после каждой инъекции цикло-фосфана, и финальную обработку цитостатиком и препаратом ДНК в момент синхронизации клеток асцита в чувствительной фазе клеточного цикла после первичных обработок. Первые три инъекции «ЦФ + ДНК» необходимы для ареста всех асцитных клеток Кребс-2 в поздней S-G2-M-фазе и их синхронного выхода в G1-S-фазе следующего клеточного цикла. Момент такого син-хронного выхода определен как принципиальная временная
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