homoharringtonine and Glioblastoma

We previously demonstrated that Annexin A2 (ANXA2) is a pivotal mediator of the pro-oncogenic features displayed by glioblastoma (GBM) tumors, the deadliest adult brain malignancies, being involved in cell stemness, proliferation and invasion, thus negatively impacting patient prognosis. Based on these results, we hypothesized that compounds able to revert ANXA2-dependent transcriptional features could be exploited as reliable treatments to inhibit GBM cell aggressiveness by hampering their proliferative and migratory potential. Transcriptional signatures obtained by the modulation of ANXA2 activity/levels were functionally mapped through the QUADrATiC bioinformatic tool for compound identification. Selected compounds were screened by cell proliferation and migration assays in primary GBM cells, and we identified Homoharringtonine (HHT) as a potent inhibitor of GBM cell motility and proliferation, without affecting their viability. A further molecular characterization of the effects displayed by HHT, confirmed its ability to inhibit a transcriptional program involved in cell migration and invasion. Moreover, we demonstrated that the multiple antitumoral effects displayed by HHT are correlated to the inhibition of a platelet derived growth factor receptor α (PDGFRα)-dependent intracellular signaling through the impairment of Signal transducer and activator of transcription 3 (STAT3) and Ras homolog family member A (RhoA) axes. Our results demonstrate that HHT may act as a potent inhibitor of cancer cell proliferation and invasion in GBM, by hampering multiple PDGFRα-dependent oncogenic signals transduced through the STAT3 and RhoA intracellular components, finally suggesting its potential transferability for achieving an effective impairment of peculiar GBM hallmarks.

Topics: Adult; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioblastoma; Homoharringtonine; Humans; Receptor, Platelet-Derived Growth Factor alpha; STAT3 Transcription Factor

A phase II trial of Homoharringtonine (HHT) was performed in 15 patients with recurrent or progressive malignant glioma. The drug was administered at a initial dose of 4 mg/m2/day by continuous 5 day intravenous infusion (3 mg/m2/day x 5 days for heavily pretreated patients). Courses were repeated every 3-4 weeks upon recovery from toxicity. No objective antitumor regressions occurred. Two patients had no change in their CT brain scans for 2-3 months and one patient had stable disease for 6 months. Toxicity was tolerable and included myelosuppression and occasionally mild hypotension. Chemosensitivity testing with HHT and several other chemotherapy drugs was performed in glioma cell lines, including cell lines derived from these patients. The results suggest that HHT is an inactive drug in malignant glioma using this dose schedule.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Brain Neoplasms; Drug Evaluation; Female; Glioblastoma; Glioma; Harringtonines; Homoharringtonine; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Tumor Cells, Cultured