Abstract
Despite substantial advances in treating cervical cancer (CC) with surgery, radiation and chemotherapy, patients with advanced CC still have poor prognosis and significantly variable clinical outcomes due to tumor recurrence and metastasis. Therefore, to develop more efficacious and specific treatments for CC remains an unmet clinical need. In this study, by virtual screening the SPECS database, we identified multiple novel JAK inhibitor candidates and validated their antitumor drug efficacies that were particularly high against CC cell lines. AH057, the best JAK inhibitor identified, effectively blocked the JAK/STAT pathways by directly inhibiting JAK1/2 kinase activities, and led to compromised cell proliferation and invasion, increased apoptosis, arrested cell cycles, and impaired tumor progression in vitro and in vivo. Next, by screening the Selleck chemical library, we identified SGI-1027, a DNMT1 inhibitor, as the compound that displayed the highest synergy with AH057. By acting on a same set of downstream effector molecules that are dually controlled by JAK1/2 and DNMT1, the combination of AH057 with SGI-1027 potently and synergistically impaired CC cell propagation via dramatically increasing apoptotic cell death and cell-cycle arrest. These findings establish a preclinical proof of concept for combating CC by dual targeting of JAK1/2 and DNMT1, and provide support for launching a clinical trial to evaluate the efficacy and safety of this drug combination in patients with CC and other malignant tumors.
Highlights
Cancer is a disease caused by abnormal proliferation and differentiation of cells that are governed by tumorigenic factors
We discovered that the combination of AH057 and a DNMT1 inhibitor SGI-1027 displayed strong synergistic antitumor effect against CC cells, raising the possibility that synergistically targeting JAK/signal transducer and activator of transcription (STAT) and DNMT1 might be a promising strategy for effectively treating CC and other human cancers
Western blot (WB) analysis verified that among the nine candidate compounds, AH057 exhibited the highest activity in reducing JAK2 phosphorylation and the phosphorylation of STAT3, an immediate downstream target of JAK2 (Fig. 1b)
Summary
Cancer is a disease caused by abnormal proliferation and differentiation of cells that are governed by tumorigenic factors. It is the second most common cause of human. To develop more efficacious and specific treatments for CC is an unmet clinical need. Compared to the severe side effects and rapidly-acquired drug resistance issues associated with routine chemotherapies[4], targeted therapies offer unique. Official journal of the Cell Death Differentiation Association. She et al Cell Death and Disease (2020)11:724 advantages including fewer side effects, improved drug effectiveness and improved quality of life. Only a few monoclonal antibody-based targeted therapies (e.g., Bevacizumab) are in clinical use for CC treatment, and a handful of small-molecule-based targeted therapies are at different phases of clinical trials[5]
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