ABSTRACT
Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognoses. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients' quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50 = 168 µM) and D283 (IC50 = 334 µM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.
Subject(s)
Antineoplastic Agents , Brain Neoplasms , Cerebellar Neoplasms , Medulloblastoma , Humans , Child , Medulloblastoma/drug therapy , Medulloblastoma/pathology , Epidermal Growth Factor/pharmacology , Epidermal Growth Factor/therapeutic use , Proto-Oncogene Proteins c-akt , Quality of Life , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Cell Proliferation , Cerebellar Neoplasms/drug therapy , ErbB Receptors/metabolism , ErbB Receptors/pharmacology , ErbB Receptors/therapeutic use , Cell Line, TumorABSTRACT
OBJECTIVE: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. METHODS: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. RESULTS: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ERK, p-ERK, cyclin D1, and brain-derived neurotrophic factor (BDNF), while enhancing p53 levels. Cell proliferation was also impaired by inhibitors of PI3K or ERK, alone or combined with AG1478. CONCLUSIONS: Our findings reveal novel aspects of EGFR regulation of ES cells and provide early evidence for antitumor activities of EGFR inhibitors in ES.
Subject(s)
Bone Neoplasms/pathology , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , ErbB Receptors/metabolism , Quinazolines/pharmacology , Sarcoma, Ewing/pathology , Tyrphostins/pharmacology , Brain-Derived Neurotrophic Factor/metabolism , Cell Line, Tumor , Cyclin D1/metabolism , Epidermal Growth Factor/pharmacology , ErbB Receptors/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation/drug effects , Signal Transduction/drug effects , Tumor Suppressor Protein p53/metabolismABSTRACT
INTRODUCTION: First-line treatment options utilizing chemotherapy and cytokine-based treatments for patients with metastatic melanoma (MM) are unsatisfactory. We analyzed the clinical outcomes of patients with MM treated in phase I trials of novel agents. We hypothesized that patients included in phase I clinical trials did not have worse outcomes than with the chemotherapy and cytokine-based first-line treatment. METHODS: Data of patients with MM treated at The Drug Development Unit between 2004 and 2010 were collected. The response rate (RR) and time to progression (TTP) for first-line therapy were compared to those of phase I trial therapy. Patients acted as their own controls for statistical analyses. RESULTS: Sixty-five patients were treated in 31 phase I trials. First-line treatment included dacarbazine or temozolomide in 58 (89%) cases and interferon-α in 5 patients (8%) and cisplatin-based treatment in 2 patients (3%). There was no significant difference in either the RR (11 vs. 14%, p = 0.87) or TTP (90 vs. 53 days, p = 0.15) in patients treated with first-line treatment versus phase I treatment, respectively. CONCLUSION: Phase I clinical trials of molecularly targeted agents show clinical activity that is not dissimilar to that of treatment with existing chemotherapy and cytokine-based treatment.
