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Hongzhang Wu,1,* Xurui Cheng,1,* Feiyan Huang,2 Gang Shao,3 Yueming Meng,1 Lingfei Wang,3 Tao Wang,1 Xiaoyuan Jia,1 Tianxin Yang,4 Xi Wang,3 Caiyun Fu1 1Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, People’s Republic of China; 2Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, People’s Republic of China; 3Department of Oncology, The 903rd Hospital of PLA, Hangzhou 310013, People’s Republic of China; 4Department of Hematology, Zhejiang Province People’s Hospital, Hangzhou 310014, People’s Republic of China*These authors contributed equally to this workCorrespondence: Caiyun Fu Email fucy03@zstu.edu.cnPurpose: Acute myeloid leukemia (AML) is a complex malignancy characterized by the clonal expansion of immature myeloid precursors. The standard treatment for newly diagnosed AML is chemotherapy consisting of cytosine arabinoside (Ara-C) and anthracyclines with disappointing clinical outcomes and severe adverse effects, such as symptomatic bradycardia, neurotoxicity. Thus, it is promising to treat AML through combination drug therapy to reduce the adverse effects of chemotherapeutics. In our recent published PNAS paper, we reported that NK-1R antagonists, both Aprepitant and SR140333, induce apoptosis of myeloid leukemia cells by inducing oxidative stress through mitochondrial calcium overload. We, therefore, tested the hypothesis of the combination Ara-C with NK-1R antagonist could enhance the efficacy of Ara-C.Methods: MTT assay was employed to detect the cell proliferation. Flow cytometry was applied to detect the cell cycle and necrosis. PI uptake and LDH release assay were used to detect the disintegration of the plasma membrane. Xenograft model was constructed to explore the effect of combination Ara-C with Aprepitant in vivo.Results: Our results showed that Aprepitant sensitizes HL60 cells to the cytotoxic effects of Ara-C more than 5-fold by enhancing G0/G1 cell cycle arrest and necrosis in vitro. Furthermore, Nec-1, a specific inhibitor of necroptosis, could recover the cell proliferative viability significantly. Attractively, once every 2-days regimen of Ara-C (5 mg/kg) and Aprepitant (10 mg/kg) via in situ injection dramatically reduced the tumor volume from 2175.0 ± 341.9 mm3 in the vehicle group to 828.4 ± 232.4 mm3 in the combination group without obvious toxicity in human myeloid leukemia xenograft mice.Conclusion: Taken together, reduced dose of Ara-C combination with moderate Aprepitant provides more effective therapeutical methods for AML treatment in vitro and in vivo with the elimination of the toxicity of Ara-C, which may pay new avenue for the usage of the routine chemotherapy drug Ara-C with low dose to enhance efficacy and reduce toxicity in clinical practice.Keywords: neurokinin receptor antagonist, cytosine arabinoside, combined chemotherapy, acute myeloid leukemia |
