homoharringtonine and Liver-Neoplasms

Homoharringtonine (HHT), was first isolated from the bark of Cephalotaxus harringtonia (Knight ex J. Forbes) K. Koch and Cephalotaxus fortunei Hook trees. The bark extract is used to treat leukemia and in recent years has also been used in traditional Chinese medicine (TCM) to treat solid tumors. However, the inhibitory mechanism of HHT in the progression of hepatocellular carcinoma (HCC) is rarely studied. We aimed to evaluate the antitumor efficacy of HHT on HCC in vitro and in vivo and elucidate the underlying molecular mechanism(s). HCC cell lines, including HCCLM3, HepG2, and Huh7, were used to evaluate the antitumor efficacy of HHT in vitro. Cytotoxicity and proliferative ability were evaluated by MTT and colony formation assays. Cell cycle progression and apoptosis in HHT-treated HCC cells were evaluated by flow cytometry. To determine the migration and invasion abilities of HCC cells, wound-healing and Transwell assays were used. Finally, western blot analysis was used to reveal the proteins involved. We also established a xenograft nude mouse model for in vivo assessments of the preclinical efficacy of HHT, mainly using hematoxylin and eosin staining, immunohistochemistry, ultrasound imaging (USI), and magnetic resonance imaging (MRI). HHT suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, and induced cell cycle arrest at the G2 phase and apoptosis. In the HCC xenograft model, HHT showed an obvious tumor-suppressive effect. Surprisingly, Slug expression was also decreased by HHT via the PI3K/AKT/GSK3β signaling pathway at least partially suppressed the growth of HCC via the PI3K/AKT/GSK3β/Slug signaling pathway.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glycogen Synthase Kinase 3 beta; Homoharringtonine; Liver Neoplasms; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays

Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in patient outcomes. Importantly, there is a paucity of preclinical HCC models in which to test new small molecules. Herein, we implemented potentially novel patient-derived organoid (PDO) and patient-derived xenografts (PDX) strategies for high-throughput drug screening. Omacetaxine, an FDA-approved drug for chronic myelogenous leukemia (CML), was found to be a top effective small molecule in HCC PDOs. Next, omacetaxine was tested against a larger cohort of 40 human HCC PDOs. Serial dilution experiments demonstrated that omacetaxine is effective at low (nanomolar) concentrations. Mechanistic studies established that omacetaxine inhibits global protein synthesis, with a disproportionate effect on short-half-life proteins. High-throughput expression screening identified molecular targets for omacetaxine, including key oncogenes, such as PLK1. In conclusion, by using an innovative strategy, we report - for the first time to our knowledge - the effectiveness of omacetaxine in HCC. In addition, we elucidate key mechanisms of omacetaxine action. Finally, we provide a proof-of-principle basis for future studies applying drug screening PDOs sequenced with candidate validation in PDX models. Clinical trials could be considered to evaluate omacetaxine in patients with HCC.

Topics: Adult; Aged; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Proliferation; Cells, Cultured; Female; Homoharringtonine; Humans; Liver; Liver Neoplasms; Male; Mice; Middle Aged; Organoids; Protein Synthesis Inhibitors; Young Adult

Topics: Animals; beta Catenin; Cadherins; Carcinoma, Hepatocellular; Cell Movement; Cell Nucleus; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Homoharringtonine; Humans; Liver Neoplasms; Male; Mice, Nude; Phosphorylation; Protein Transport; Receptor, EphB4; Transforming Growth Factor beta

To make full use of cephalotaxus plant resources and search for antitumor agents with higher activities and lower side effects.. The C3 hydroxy groups of the cephlotaxine and drupacine were acylated by taxol side chain and its isomers to give a series of derivatives of cephlotaxine and drupacine.. Six novel alkaloid esters were designed and synthesized. The pharmacological screening results showed that VIIIa, VIIIb, IXa and IXc exhibited significant activities on KB, HCT and Bel in vitro.. Novel alkaloid esters are worthy to be intensively studied.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Colonic Neoplasms; Harringtonines; Homoharringtonine; Humans; KB Cells; Liver Neoplasms; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line; Cells, Cultured; Colony-Forming Units Assay; Drug Evaluation, Preclinical; Flavones; Flavonoids; Harringtonines; Homoharringtonine; Humans; Liver Neoplasms; Tumor Stem Cell Assay