However, mice treated with LY294002 showed slight thrombocytopeni

However, mice treated with LY294002 showed slight thrombocytopenia. We also measured the levels of the biochemical enzymes alanine aminotransferase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), glucose, and blood urea nitrogen in mice treated with vehicle, BO-1509, LY294002, and the combination of BO-1509 and LY294002. As shown in Table 2, AST levels were slightly increased in mice treated with LY294002, whereas LDH levels were PI3K inhibitor drugs increased in the sera of the combination-treated mice. These results indicate limited toxicity for BO-1509 applied alone

and in combination with LY294002 in mice. Derivatives of 3a-aza-cyclopenta[a]indenes are synthetic bifunctional alkylating agents that induce ICLs in DNA and are potent anticancer agents [30] and [31]. ICLs may cause replication-dependent DSB formation in DNA [4] and [48]. Cells undergo apoptosis if DNA DSBs are not repaired [4]. BO-1509 was synthesized through lead optimization of BO-1012, which was previously reported to have potent MG-132 nmr antitumor activity both in vitro and in tumor xenograft

models. In the present study, we found that BO-1509 was more cytotoxic to H460 cells than BO-1012 (IC50 = 63.8 μM) [28]. We also demonstrated that treatment of various human lung cancer cells with BO-1509 resulted in an increase in γH2AX protein (a well-established marker of DNA DSB) levels together with nuclear foci formation. Multiple repair pathways, check including HR and NHEJ [4], are activated in response to the formation of DSB. In the four lung cancer cell lines examined, BO-1509 treatment activated Nbs1 and enhanced the expression and nuclear translocation of Rad51. However, the response of other repair components, such as Mre11 and FANCD2, to BO-1509–induced damage was different in different cell lines. The MRN complex functions as a DNA damage

sensor [49], where FANCD2, a member of Fanconi anemia family that is an inherited genomic instability disorder, coordinates HR, nucleotide excision repair, and mutagenic translesion synthesis [50] and [51]. However, it is unclear why they have differential responses to DNA damage in different cell lines and it warrants our further investigation. LY294002, an inhibitor of PI3K signaling, significantly suppressed BO-1509–activated DNA repair protein levels and synergistically enhanced the cytotoxicity of BO-1509 in all of the cell lines that were studied. Inhibition of DNA repair pathway regulatory signaling is therefore a rational strategy for cancer treatment. It has been reported that PI3K mediates the activation of ATM to facilitate DNA repair when DNA damage is induced by ionizing radiation [52]. LY294002 has been evaluated in various cell lines for its ability to inhibit all major subclasses of PI3K and PI3K-like kinases (ATM, ataxia telangiectasia and rad3 related, and DNA-dependent protein kinase) [27].

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