Baicalein, Ethyl Acetate, and Chloroform Extracts of Scutellaria baicalensis

This study rated antiviral activity of Scutellaria baicalensis Georgi (S. baicalensis) extracts against influenza A virus subtypes, for example, pandemic 2009 H1N1, seasonal H1N1 and H3N2. Ethyl acetate (EtOAc) and chloroform extracts inhibited in vitro neuraminidase (NA) enzymatic activity and viral replication more than methanol (MeOH) extract. EtOAc extract demonstrated NA inhibition IC50 values ranging from 73.16 to 487.40 μg/mL and plaque reduction IC50 values ranging from 23.7 to 27.4 μg/mL. Chloroform extract showed antiviral activities with plaque reduction IC50 values ranging from 14.16 to 41.49 μg/mL Time-of-addition assay indicated that EtOAc and chloroform extracts also significantly inhibited virus yields after infection. HPLC analysis demonstrated that baicalin was dominant in the MeOH extract; baicalein and chrysin were rich in the EtOAc and chloroform extracts. Molecular simulation revealed baicalein hydrogen bonding with Glu277 as well as hydrophobic and Van der Waals interactions with Ile222, Arg224, Ser246, and Tyr347 in NA1 active sites of NA1. Baicalein inhibited in vitro replication of influenza A viruses pandemic 2009 H1N1 (IC50 = 0.018 μM) and seasonal 2007 H1N1 using plaque reduction assays. A combination of low-dose baicalein with other anti-influenza agents could be applicable for development of alternative remedies treating influenza A virus infection

MJ-66 induces malignant glioma cells G2/M phase arrest and mitotic catastrophe through regulation of cyclin B1/Cdk1 complex

Malignant gliomas are among the most devastating cancers as they are resistant to many kinds of treatment. Despite recent advances in the diagnosis and treatment, the prognosis of patients remains very poor and the development of new drug is urgently needed. Here, we report that a synthetic quinazolinone analog 2-(naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (MJ-66) induced glioma cell death. Immunofluorescence staining showed that MJ-66-induced cell death was associated with multinucleated phenotype and multipolar spindles that were typical characteristics of mitotic catastrophe. Flow cytometry analysis revealed that MJ-66 caused glioma cell cycle arrest at G2/M phase and increased the proportion of polyploidy cells. Western blotting indicated that the expression of cyclin B1, Cdk1 pY15 and Cdk1 increased after treatment with MJ-66. MJ-66 effectively inhibited tumor growth and induced apoptosis in the xenograft animal model of U87 human glioma cells. Together, these results suggest that MJ-66 inhibited malignant gliomas growth through inducing mitotic catastrophe by interference with G2/M cell cycle checkpoint which may open a new avenue for the treatment of malignant gliomas

Novel Quinazolinone MJ-29 Triggers Endoplasmic Reticulum Stress and Intrinsic Apoptosis in Murine Leukemia WEHI-3 Cells and Inhibits Leukemic Mice

The present study was to explore the biological responses of the newly compound, MJ-29 in murine myelomonocytic leukemia WEHI-3 cells in vitro and in vivo fates. We focused on the in vitro effects of MJ-29 on ER stress and mitochondria-dependent apoptotic death in WEHI-3 cells, and to hypothesize that MJ-29 might fully impair the orthotopic leukemic mice. Our results indicated that a concentration-dependent decrease of cell viability was shown in MJ-29-treated cells. DNA content was examined utilizing flow cytometry, whereas apoptotic populations were determined using annexin V/PI, DAPI staining and TUNEL assay. Increasing vital factors of mitochondrial dysfunction by MJ-29 were further investigated. Thus, MJ-29-provaked apoptosis of WEHI-3 cells is mediated through the intrinsic pathway. Importantly, intracellular Ca2+ release and ER stress-associated signaling also contributed to MJ-29-triggered cell apoptosis. We found that MJ-29 stimulated the protein levels of calpain 1, CHOP and p-eIF2α pathways in WEHI-3 cells. In in vivo experiments, intraperitoneal administration of MJ-29 significantly improved the total survival rate, enhanced body weight and attenuated enlarged spleen and liver tissues in leukemic mice. The infiltration of immature myeloblastic cells into splenic red pulp was reduced in MJ-29-treated leukemic mice. Moreover, MJ-29 increased the differentiations of T and B cells but decreased that of macrophages and monocytes. Additionally, MJ-29-stimulated immune responses might be involved in anti-leukemic activity in vivo. Based on these observations, MJ-29 suppresses WEHI-3 cells in vitro and in vivo, and it is proposed that this potent and selective agent could be a new chemotherapeutic candidate for anti-leukemia in the future

Synthesis and Antiplatelet Activity of Alkoxy Derivatives of 2- Phenylquinazolines

A series of 4-alkoxy-2-phenylquinazoline and N3-alky1-2- phenylquinazolinone derivatives were prepared by alkylation of various 2- phenylquinazolinones (1-5). The 4-alkoxy derivatives with lower alkyls, such as methyl and ethyl groups, significantly inhibited AA-induced platelet aggregation. In contrast, all the corresponding N3 -alkyl derivatives demonstrated very weak activity. Among the 4- alkoxy derivatives investigated, 4-ethoxy-2- phenylquinazoline (7) displayed the best activity with an IC 50 value of about 1.60 μM, about 13 times the potency of aspirin. Since the chemical structure of compound 7 is quite distinct from known anti platelet agents, the mechanism of action of compound 7 is currently under investigation

Abstract 5103: Development of MJ-66 as a novel anticancer agent for the treatment of malignant gliomas

Abstract Malignant glioma is the most common aggressive adult primary tumor of the central nervous system. Treatments of malignant gliomas include surgery, radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. However, inherent- and acquired resistance to TMZ present major obstacles to successful treatment, and the prognosis of patients with malignant gliomas remains very poor. MJ-66, a synthetic qunazoline compound, was identified in our study as a potent anti-proliferative agent especially on human glioma with IC50 of approximately 60 nM. In intracranial glioma xenograft model, MJ-66 (0.14 mg/kg in saline, i.p., q.d., 10 days) significantly inhibited tumor growth and increased the survival of the experimental mice, however, did not decrease the body weight of mice. Currently, there is a profound unmet medical need for a new drug in the treatment of malignant brain tumor. The MJ-66 demonstrated superior efficacy to TMZ that are the only first-line-drug in clinical use. MJ-66 is suggested to be a promising anticancer candidate. Note: This abstract was not presented at the meeting. Citation Format: Mann-Jen Hour, Tai-Lin Chen, Po-Wu Gean, Hong-Zin Lee. Development of MJ-66 as a novel anticancer agent for the treatment of malignant gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5103. doi:10.1158/1538-7445.AM2017-5103</jats:p

Clinical impact of tetracyclines and/or proton pump inhibitors on the efficacy of epidermal growth factor receptor inhibitors in non-small cell lung cancer: a retrospective cohort study

Abstract Background This retrospective cohort study examined the impact of tetracyclines (TCs) and proton pump inhibitors (PPIs) alone or in combination on the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). Methods Patients with NSCLC treated with gefitinib or erlotinib for at least 1 week between January 2009 and October 2021 were enrolled and divided into four groups based on the presence/absence of TC and/or PPI in the therapeutic regimen: TC-/PPI-, TC + /PPI-, TC-/PPI + , TC + /PPI + . Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively. Results The estimated median PFS and OS of 347 included patients with NSCLC were 8.57 (95% confidence interval [CI]: 7.66–9.48) months and 13.10 (95% CI: 11.03–15.17) months, respectively. Co-administration of EGFR-TKIs with PPIs decreased the PFS and OS, while that with TCs improved the PFS and OS. However, the concomitant use of EGFR-TKIs, TCs, and PPIs yielded survival rates similar to that of EGFR-TKI therapy alone. Conclusions The administration of EGFR-TKIs with other drugs poses a challenge in managing patients with NSCLC. Therefore, reassessing the indications and necessity of TC or PPI therapy is essential for patients receiving erlotinib or gefitinib. The benefits and risks of possible discontinuation due to the clinical relevance of this interaction should be considered. </jats:sec