Combined inhibition of JAK1/2 and DNMT1 by newly identified small-molecule compounds synergistically suppresses the survival and proliferation of cervical cancer cells

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.

Distinct immune-effector and metabolic profile of CD8+ T Cells in patients with autoimmune polyarthritis induced by therapy with immune-checkpoint inhibitors

“…Thus, finding other therapeutic strategies to curb ICI-induced musculoskeletal inflammation and maintain antitumor activity will be required to meet current clinical needs in the management of ICI-irAEs. Preclinical studies on human cancer cell lines have shown that JAK-pathway inhibition impairs tumor growth [35,36]. Still, new data on increased risk of malignancy in RA patients associated with Tofacitinib use put the previously favourable assessment of JAKi in vitro and in vivo into question [37,38].…”

Association Between SNPs in the One-Carbon Metabolism Pathway and the Risk of Female Breast Cancer in a Chinese Population

“…34,35 Moreover, we found that DNMT1 rs16999593 was more common in patients with TNM stage 0-II, no lymph-node metastasis and negative expression of HER2, which indicates that DNMT1 could regulate gene expression in an epigenetic manner, resulting in the pathological characteristics of cancers. [36][37][38] Functionally, rs16999593, a missense variant, changes from T to C in amino acid 97 (histidine to arginine), which may disrupt the function of DNMT1, thereby increasing the susceptibility to cancer; 35 however, the function of substitution caused by the polymorphism is still unclear. In addition, our results showed that DNMT1 rs2228611 was a protective risk factor for BC patients.…”

DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application

“…SGI-1027 may inhibit DNMT activity, induce the degradation of DNMT1 and reactivate tumor suppressor genes [ 69 ]. SGI-1027 can also impair cervical cancer cell and hepatocellular carcinoma cell propagation by dramatically increasing apoptotic cell death and cell cycle arrest [ 69 , 70 ]. As a novel DNMT inhibitor, MC3343 is more potent and selective than SGI-1027 toward other S-adenosylhomocysteine-dependent (SAM-dependent) methyltransferases [ 71 , 72 ].…”