These studies have shown that LY294002 can overcome the problem of drug resistance [53] and increase the efficacy of individual drugs in mouse tumor xenograft models [25] and [26]. Our present study has shown that LY294002 is able to enhance the killing effects of BO-1509. We also demonstrated that LY294002 mediates its effects through suppression of Nbs1 and Rad51, which are involved in the HR repair pathway [54], [55], [56] and [57]. see more In addition, Nbs1 is not only a core member of the MRN complex that tethers DSB ends and recruits

other proteins to conduct HR and NHEJ repair [7], [58] and [59] but also plays specific roles in the activation of ATM and its downstream targets to trigger a second wave of repair [60]. In the present animal study, LY294002 alone did not induce any significant tumor reduction, with

the exception of the PC9/gef B4 xenografts. In contrast, LY294002 enhanced the antitumor activity of BO-1509 in various lung cancer xenografts. The main goals of synergistic therapeutics are to decrease the dose of the individual drugs, Veliparib molecular weight reduce toxicity, minimize or delay the induction of drug resistance, and overcome the problem of drug resistance [61], and combination drug therapies have frequently been used for the treatment of a variety of cancers. Hematopoietic toxicity is major side effect of DNA-alkylating agents [62] and [63]. Similar to other alkylating agents, the treatment of mice with

BO-1509 alone or in combination with LY294002 resulted in a moderate suppression of bone marrow–derived cells (i.e., a decrease in white blood cells (WBCs), RBCs, and hemoglobin). Although most alkylating agents cause a decrease in platelet count [62] and [63] as one of their side effects, BO-1509 did not suppress the platelet count. Furthermore, no major pathologic changes were observed in mice treated with the drugs alone or in combination. The combination of BO-1509 and LY294002 suppressed tumor metastasis, L-gulonolactone oxidase which is a crucial determinant of chemotherapy failure. Because LY294002 is not suitable for clinical use, the therapeutic efficacy of BO-1509 combined with other clinically approved PI3K inhibitors warrants further investigation. Lung cancer is a major cause of cancer death and accounts for approximately 13% of all cancer deaths around the world because of its high incidence and mortality rates [64]. NSCLC contributes to approximately 85% of all lung cancers [38] and [65]. DNA-damaging drugs such as cisplatin, carboplatin, mitomycin C, and paclitaxel are typically the first lines of treatment for NSCLC, either alone or in combination [38] and [66]. However, less than 30% of patients respond to platinum-based chemotherapy. The main reason for the nonresponsiveness of chemotherapeutic agents in NSCLC is the intrinsic resistance to chemotherapy and radiation therapy [31].