Co-treatment of Low Dose Pacritinib, a Phase III Jak2 Inhibitor, Greatly Increases Apoptosis of P-gp Over-expressing Cancer Cells With Multidrug Resistance

Article

Author: Lee, Jin-Sol ; Kim, Hyung Sik ; Oh, Yunmoon ; Yoon, Sungpil ; Park, Jae Hyeon ; Lee, Ji Sun

BACKGROUND/AIMThe over-expression of P-glycoprotein (P-gp) is a major mechanism underlying multidrug resistance (MDR). Co-treatment with Janus kinase 2 (Jak2) inhibitors sensitizes P-gp-over-expressing drug-resistant cancer cells. In this study, we evaluated pacritinib, a Jak2 inhibitor currently in phase III clinical trials.MATERIALS AND METHODSMicroscopic observation, cell viability assay, colony forming assay, rhodamine uptake tests, annexin V analyses, fluorescence-activated cell sorting (FACS), and western-blot analysis were performed to further investigate the mechanism of action.RESULTSWe found that pacritinib reduced cell viability, induced G₂ arrest, and upregulated early apoptosis when administered to P-gp-over-expressing resistant KBV20C cells with vincristine (VIC). Moreover, apoptosis and G₂ arrest in VIC-pacritinib-treated cells were involved in the upregulation of pH2AX expression. Pacritinib had an approximately 2-fold higher P-gp-inhibitory activity than the dimethyl sulfoxide (DMSO)-treated control, indicating that VIC-pacritinib sensitization involves the P-gp-inhibitory effects of pacritinib. Similar to VIC, other antimitotic drugs (vinorelbine, vinblastine, and eribulin) could also sensitize against KBV20C cells by co-treatment with pacritinib. Furthermore, comparison of pacritinib with previously characterized Jak2 inhibitors revealed that the VIC-pacritinib combination had sensitization effects similar to those of VIC- CEP-33779 or VIC-NVP-BSK805 combinations at lower doses in KBV20C cells. Generally, Jak2 inhibitor and VIC co-treatment sensitized P-gp-over-expressing resistant cancer cells by inducing early apoptosis.CONCLUSIONCollectively, pacritinib, induced G₂ arrest, reduced cell viability, had high P-gp inhibitory activity, and upregulated the expression of pH2AX when used in combination with VIC. As pacritinib is a Jak2 inhibitor currently in phase III clinical trials, our findings may facilitate the application of this co-treatment in patients with MDR cancer.

01 May 2021·Journal of Infection and ChemotherapyQ4 · MEDICINE

Identification of disulfiram as a potential antifungal drug by screening small molecular libraries

Q4 · MEDICINE

Article

Author: Ge, Xuejun ; Hao, Weifeng ; Du, Ning ; Zhang, Heyu ; Qiao, Dan ; Li, Xuefen ; Han, Ying ; Fan, Yufeng

OBJECTIVESCandida albicans and Candida auris strains are common causative species of Candidiasis. The limited number of antifungal drugs and the current situation of resistance to existing antifungals force us to search for new antifungal alternatives.METHODSIn this work, primary screening of small molecule libraries (Metabolism Compound Library and Epigenetics Compound Library) consisting of 584 compounds against Candida albicans SC5314 was performed. The dose-response assays, XTT assays, scanning electron microscopy and confocal laser scanning microscopy were used to confirm the antifungal activities of the selected compounds against Candida strains.RESULTSThrough the primary screening, we identified five compounds (U73122, disulfiram, BSK805, BIX01294, and GSKJ4) that inhibited strains growth ≥ 80% for dose-response assays. Disulfiram was identified as the most potent repositionable antifungal drug with 50% growth inhibition detected at a concentration as low as 1 mg/L. The further results showed the antifungal activity of disulfiram against biofilm formation of Candida strains with a 50% minimum inhibitory concentration ranging from 32 to 128 mg/L. Further observations by scanning electron microscopy and confocal laser scanning microscopy confirmed the destruction of biofilm architecture and the change of biofilm morphology after being exposed to disulfiram.CONCLUSIONThe study indicated the potential clinical application of disulfiram as a promising antifungal drug against candidiasis.

01 Jun 2020·Molecular Therapy - OncolyticsQ2 · MEDICINE

Stomatin-like Protein 2 Promotes Tumor Cell Survival by Activating the JAK2-STAT3-PIM1 Pathway, Suggesting a Novel Therapy in CRC

Q2 · MEDICINE

ArticleOA

Author: Wu, Chao ; Lu, Shasha ; Wang, Lisha ; Liu, Zebing ; Ye, Xuanguang ; Li, Anqi ; Zhao, Ling ; Zhao, Huiyong ; He, Wei ; Liu, Qiang ; Shen, Xiaohan ; Xiao, Xiuying

Despite intensive efforts, a considerable proportion of colorectal cancer (CRC) patients develop local recurrence and distant metastasis. Stomatin-like protein 2 (SLP-2), a member of the highly conserved stomatin superfamily, is upregulated across cancer types. However, the biological and functional roles of SLP-2 remain elusive in CRC. Here, we report that high SLP-2 expression was found in CRC tissues and was linked to tumor progression and tumor cell differentiation. Additionally, high SLP-2 expression correlated with poor overall survival (OS) in CRC patients (p < 0.001). SLP-2 knockout (SLP-2KO), generated by CRISPR/Cas9, reduced cell growth, migration, and invasion; induced apoptosis in CRC cells; and reduced tumor xenograft growth in vivo. A 181-compound library screening showed that SLP-2KO produced resistance to JAK2 inhibitors (NVP-BSK805 and TG-101348) and a PIM1 inhibitor (SGI-1776), revealing that the JAK2-STAT3-PIM1 oncogenic pathway was potentially controlled by SLP-2 in CRC. In vitro and in vivo, TG-101348 combined with SGI-1776 was synergistic in CRC (combination index [CI] < 1). Overall, our findings suggest that SLP-2 controls the JAK2-STAT3-PIM1 oncogenic pathway, offering a rationale for a novel therapeutic strategy with combined SGI-1776 and TG-101348 in CRC. Additionally, SLP-2 may be a prognostic marker and biomarker for sensitivity to JAK2 and PIM1 inhibitors.

100 Deals associated with BVB-808

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