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Theranostics Novel Hybrid Molecule Overcomes the Limited Response Of Theranostics 2018, Vol. 8, Issue 18 4995 Ivyspring International Publisher Theranostics 2018; 8(18): 4995-5011. doi: 10.7150/thno.26627 Research Paper Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling Zhi Huang,1# Wei Zhou,1# Yongtao Li,1 Mei Cao, 1 Tianqi Wang, 1 Yakun Ma, 1 Qingxiang Guo, 1 Xin Wang,1 Chao Zhang,1 Chenglan Zhang,1 Wenzhi Shen,6 Yanhua Liu,2 Yanan Chen,2 Jianyu Zheng,5 Shengyong 4 1,2,3 1,2,3 Yang, Yan Fan and Rong Xiang 1. Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin 300071, China 2. State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China 3. 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, Tianjin 300071, China 4. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy and Sichuan University, Chengdu 610041, China 5. State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China 6. Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining 272067, China. # Zhi Huang and Wei Zhou contributed equally to this work. Corresponding authors: Yan Fan: E-mail: [email protected]; Rong Xiang: E-mail: [email protected]. © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.04.11; Accepted: 2018.09.08; Published: 2018.10.05 Abstract Despite initial progress in preclinical models, most known histone deacetylase inhibitors (HDACis) used as a single agent have failed to show clinical benefits in nearly all types of solid tumours. Hence, the efficacy of HDACis in solid tumours remains uncertain. Herein, we developed a hybrid HDAC inhibitor that sensitized solid tumours to HDAC-targeted treatment. Methods: A hybrid molecule, Roxyl-zhc-84 was designed and synthesized with novel architecture. The pharmacokinetics and toxicity of Roxyl-zhc-84 were analysed. The antitumour effects of Roxyl-zhc-84 on solid tumours were investigated by assessing cell growth, apoptosis and cell cycle in vitro and in three in vivo mouse models and compared to those of corresponding control inhibitors alone or in combination. Gene set enrichment analysis was performed, and relevant JAK1-STAT3-BCL2 signalling was identified in vitro and in vivo in mechanistic studies. Results: Roxyl-zhc-84 showed excellent pharmacokinetics and low toxicity. The novel hybrid inhibitor Roxyl-zhc-84 induced cell apoptosis and G1-phase arrest in breast cancer and ovarian cancer cell lines. In three mouse models, oral administration of Roxyl-zhc-84 led to significant tumour regression without obvious toxicity. Moreover, Roxyl-zhc-84 dramatically improved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance. Roxyl-zhc-84 treatment exhibited vastly superior efficacy than the combination of HDAC and JAK1 inhibitors both in vitro and in vivo. Conclusion: Concurrent inhibition of HDAC and CDK using Roxyl-zhc-84 with additional JAK1 targeting resolved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance, providing a rational multi-target treatment to sensitize solid tumours to HDACi therapy. Key words: HDAC1, CDK4/6, JAK1, inhibitor, solid tumour Introduction Cancer is a complex multigenic disease cancer offers an opportunity for drug combination involving complicated signalling networks and treatments that target two or more pathways. Hybrid multiple cellular pathways [1]. This characteristic of molecules, which are made using two different http://www.thno.org Theranostics 2018, Vol. 8, Issue 18 4996 molecular units from independently acting drugs To overcome the weakness of HDACis in solid with different pharmacological effects, have recently tumours, we proposed a hybrid molecule strategy risen in significance [2, 3]. Strategies using hybrid [25]. Activity recognition is a key property for hybrid molecules avoid the use of expensive and molecules [26, 27], so to identify synergistic time-consuming optimization trials in determine the combinations [28] with HDACis, we examined our best drug combinations. These hybrid molecules selective inhibitors. From these experiments, we display enhanced pharmacological properties, are of determined that vorinostat [29], a pan-HDAC novel architecture and have been applied as a inhibitor, was significantly synergistic with standard treatment for cancer to overcome drug abemaciclib [30], a CDK4/6 inhibitor [31] (Figure S1). resistance, reduce side effects and so on [4]. Cyclin-dependent kinases (CDKs) are protein kinases Histone deacetylases (HDACs) regulate involved in important cellular processes, such as cell chromatin remodelling, gene transcription, and the cycle or transcription regulation. The first gap phase, activity of partner proteins, controlling cell growth, G1, of the cell cycle comprises important preliminary cell cycle regulation, DNA mismatch repair, steps for the initiation of DNA replication and proliferation and apoptosis [5, 6]. HDAC over- subsequent cell division in human embryogenesis and expression has been identified in a variety of human homeostasis, as well as in cancer development. In cancers, including haematological neoplasms and particular, CDK4/6 functions as a critical activator of solid tumours. Association of HDACs with oncogenic G1 phase progression. The aim of therapeutic DNA-binding fusion proteins and other repressive CDK4/6 targeting in cancer cells is to stop cell transcription factors constitutively restrains the proliferation and restore cell cycle arrest in G1 phase, expression of specific tumour suppressor genes. while minimizing or avoiding adverse side effects for Therefore, HDACs represent a rational target for cancer patients. cancer treatment. As a result, the use of HDACis in In this context, we designed and synthesized a cancer therapy is an area of active investigation. series of novel hybrid compounds, including two HDACis selectively alter gene transcription and essential pharmacophoric elements for HDAC and represent the first successful epigenetic-based cancer CDK, to identify combination solutions and augment therapy [7, 8]. Several HDACis have been approved response of HDACis in solid tumours [32]. As for cancer treatment by the FDA and have been indicated by the suppression of HDAC and CDK, the shown to have clinical benefits in multi-type hybrid molecule Roxyl-zhc-84 exhibits remarkable haematological malignancies [9-11]. Vorinostat is antitumour activity both in vitro and in vivo (Figure approved for the treatment of cutaneous T-cell S1). Insight into the mechanism of this novel hybrid lymphoma (CTCL). Romidepsin is approved for the inhibitor solution revealed potent induction of treatment of CTCL and peripheral T-cell lymphoma apoptosis via overcoming JAK1-STAT3-BCL2- (PTCL) [12]. Belinostat is approved for the treatment mediated drug resistance. of relapsed or refractory PTCL, and panobinostat is approved for the treatment of multiple myeloma Methods (MM) [13]. Despite some progress in clinical trials, Cell lines and culture conditions most known HDACis have failed to show clinical Murine and human cancer cell lines (4T1, benefits in nearly all types of solid tumours, such as MDA-MB-231, MDA-MB-468, SK-OV-3, OVCAR-5 breast cancer, renal cancer and prostate cancer [11, and H460) were obtained from the American Type 14-16]. Hence, the efficacy of HDACis in solid Culture Collection (ATCC). All cell lines were recently tumours remains unsatisfying [17, 18], such as for the authenticated by cellular morphology and short approved pan-HDAC inhibitor vorinostat. tandem repeat analysis at Microread Inc. (Beijing, Meanwhile, a lack of solid tumour uptake and China) according to guidelines from the ATCC. extensive tissue distribution has resulted in clinical MDA-MB-231 and MDA-MB-468 cells were cultured ineffectiveness and off-target effects, such as in Leibovitz's L-15 medium (Biological Industries, myelosuppression, fatigue, and cardiac toxicity [19, Israel) at 37 °C in a 0.2% CO2 incubator. 4T1, SK-OV-3, 20]. The synergistic effects of HDAC inhibitors with OVCAR-5 and H460 cells were cultured in RPMI 1640 other antitumour agents is an ideal strategy to use medium at 37 °C in a 5% CO2 incubator. All medium multifunctional inhibitors to simultaneously interact was supplemented with 10% fetal bovine serum with multiple targets with high potency and (FBS), 100 unit/mL penicillin and 100 μg/mL acceptable toxicity. Recent progress has shown streptomycin. success in combining the HDAC pharmacophore with other enzyme inhibitor activities, such as kinases Immunoblotting analysis [21-24]. Immunoblotting analysis was conducted as http://www.thno.org Theranostics 2018, Vol. 8, Issue 18 4997 previously described [33]. Compound-treated cells mg/kg), abemaciclib (60 mg/kg), and filgotinib (60 were resuspended in RIPA lysis buffer. After mg/kg) were given orally daily for the number of centrifugation at 16,200 g for 10 min at 4 °C, days indicated. For combination treatment, two drugs supernatants were collected in a pre-cooled
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