This interpretation is additional supported from the truth Methyclothiazide that in our investigation, typical mitotic figures had been only observed exceptionally in etoposide exposed cells, whereas nuclei presenting atypical morphology were rather abundant. On top of that, the TUNEL optimistic cells have been more abundant following treatment method in comparison using the cells presenting biochemical features of cell death in the annexin V/PI assay. There exists clear evidence that endo polyploidization in senescent cell popula tion constitutes a consequence of re replication of ge nomically damaged G2/M cells. At the identical time, independent karyoplasts/reproductive genome lowered subcells may perhaps type from giant polyploid cells by means of some type of reductional division, leading to increased gen etic variation.
What is a lot more, induction of DNA injury in cancer cell lines was established to be associated not only to endopolyploidy and depolyploidization, but in addition to overexpression of meiosis specific genes and mobili zation of their goods on the sites strategic for division. More not long ago it has also been reported that al even though you can find some morphological and biochemical characteristics of senescence at the same time as growth arrest within the population of A549 cells exposed to topoisomerase II inhibitors, long-term results from the treatment in clude a re development of the fraction of population originating most possibly from cancer stem cells. Within this sit uation, a relatively much more prolonged, but still rever sible development arrest in the population occurred soon after inhibition of your DNA harm response pathway.
On account of the truth that 24 h after exposure to etoposide we nevertheless observed a comparatively high variety of TUNEL positive cells in comparison with those annexin V/PI constructive, this pathway was most most likely energetic in our experiment also. Therefore, some alterations in heterochromatin options, like gluey or stick heterochromatin in near senescent population of cultured cells, appear to be accountable for mitotic failure and chromosomal instability. Ana logically, etoposide may perhaps induce impairments in untan gling of chromatin, which in flip interferes using the right formation of chromosomes and the decatenation of chromatids, main most likely to the identical ultimate outcome, i. e. induction of the senescent like pheno type while in the cancer cell population in addition to increased polyploidy and genetic instability, as well as heterogen eity with the response.
What is much more, an unstable senes cence plan induced in cancer cell populations by DNA damage is considered to get linked to a phenomenon corresponding to your above described series of events, and termed neosis. The truth is this course of action might con tribute to chemotherapy resistance, on account of the truth that greater instability coupled with repeated cycles of self renewal may perhaps favour the accumulation of survival selling mutations and also the growth of a lot more inva sive subclones, especially underneath constant get in touch with that has a chemotherapeutic drug.