homoharringtonine and Urinary-Bladder-Neoplasms

The application of immune checkpoint inhibitors and FGFR protein tyrosine kinase inhibitors have made a tremendous breakthrough in bladder cancer therapy. However, inadequate drug responses and drug resistance interfere with successful treatment outcomes. For a new drug to enter the market, there is a long development cycle with high costs and low success rates. Repurposing previously Food and Drug Administration (FDA)-approved medications and using novel drug discovery strategies may be an optimal approach. Homoharringtonine (HHT) has been used for hematologic malignancies for over 40 years in China and was approved by the FDA approximately 10 years ago. Many studies have demonstrated that HHT effectively inhibits the development of several types of solid tumors, although the underlying mechanisms of action are unclear. In this study, we investigated the mechanisms underlying HHT activity against bladder cancer growth. We first compared HTT with the drugs currently used clinically for bladder cancer treatment. HHT showed stronger inhibitory activity than cisplatin, carboplatin, and doxorubicin. Our in vitro and in vivo data demonstrated that HHT inhibited proliferation, colony formation, migration, and cell adhesion of bladder cancer cells and induced apoptosis and cell cycle arrest in the nanomolar concentration range. Furthermore, we revealed that HHT treatment could downregulate the MAPK/Erk and PI3k/Akt signaling pathways by inactivating the integrin α5/β1-FAK/Src axis. HHT-induced activity reduced cell-ECM interactions and cell migration, thus suppressing tumor metastasis progression. Altogether, HHT shows enormous potential as an anticancer agent and may be applied as a combination treatment strategy for bladder cancer.

Topics: Apoptosis; Cell Line, Tumor; Homoharringtonine; Humans; Integrin alpha5; Integrin alpha5beta1; Pharmaceutical Preparations; Phosphatidylinositol 3-Kinases; Urinary Bladder Neoplasms

Rates of [3H]glucosamine and mannose incorporation into glycoproteins and dolichol-linked oligosaccharides in exponentially growing T-24 bladder cancer cells were examined after exposure to homoharringtonine (HHT). Two-h treatment of HHT (10 ng/ml) reduced [3H]glucosamine and mannose incorporation into the glycoproteins to 61% and 32% of controls. Concomitantly, respective sugar incorporation into dolichol-linked oligosaccharides was elevated 29% and 30% above control. The maximal inhibition of glycoprotein biosynthesis and stimulation of the lipid-linked oligosaccharides occurred within 2 to 4 h after exposure to 50 ng/ml of the drug. Prolonged drug exposure (greater than 8 h) resulted in generalized suppression of glycoprotein biosynthesis and lipid-linked oligosaccharide formation. The kinetic study indicated that the time course on reduction of glycoprotein biosynthesis and accumulation of dolichol-linked oligosaccharides paralleled the decline in protein synthesis. Further, the inhibition of glycoprotein synthesis and stimulation of dolichol-linked oligosaccharides were reversible 4 h after drug withdrawal. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiographic analysis of the [3H]mannose-labeled glycoprotein revealed no pronounced difference between HHT-treated and control cells. These data suggest that the inhibition of glycosylation results from combined decrease of acceptors for glycoprotein biosynthesis with a simultaneous accumulation of the dolichol-linked oligosaccharides. Collectively these data may account for many of the HHT-induced bioresponses.

Topics: Alkaloids; Carcinoma, Transitional Cell; Cell Division; Cyclophosphamide; Electrophoresis, Polyacrylamide Gel; Glycoproteins; Glycosylation; Harringtonines; Homoharringtonine; Humans; Proteins; Tumor Cells, Cultured; Tunicamycin; Urinary Bladder Neoplasms