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Background: Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic. Methods: MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis. Results: We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model. Conclusions: Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Female mammals have a limited reproductive lifespan determined by the size of the primordial follicle pool established perinatally. Over two thirds of fetal oocytes are abolished via programmed cell death during early folliculogenesis. However, the underlying mechanisms governing fetal oocyte attrition remain largely elusive. Results: Here, we demonstrate that glycogen synthase kinase-3 beta (GSK-3β) is indispensable for fetal oocyte maintenance during meiotic prophase I in mice. In vitro inhibition of GSK-3β activity or in vivo conditional deletion of Gsk-3β in the germline led to a dramatic loss of fetal oocytes via apoptosis, which subsequently resulted in a reduced capacity of the primordial follicle pool. Inhibition of GSK-3β also impeded meiotic progression in fetal oocytes and led to a deficiency in DNA double-strand break (DSB) repair associated with premature upregulation of Tap63, the major genome guardian of the female germline, following GSK-3β inhibition in fetal ovaries. Mechanistically, we demonstrated that aberrant nuclear translocation of β-catenin was responsible for the abnormal expression of TAp63 and global fetal oocyte attrition following GSK-3β inhibition. Conclusions: In summary, GSK-3β was essential for sustaining fetal oocyte survival and folliculogenesis via fine-tuning the cytoplasmic-nuclear translocation of β-catenin, which in turn modulates timely TAp63 expression during meiotic prophase I in mice. Our study provides a perspective on the physiological regulatory role of DNA damage checkpoint signaling in fetal oocyte guardianship and female fertility. [ABSTRACT FROM AUTHOR]