The Antiproliferative and Pro-apoptotic Effects of Methoxyamine on Pediatric Medulloblastoma Cell Lines Exposed to Ionizing Radiation and Chemotherapy.

Abstract

Medulloblastoma (MB) treatment is continuously evolving. Better treatment approaches, focused on particular molecular pathways involved in MB development and progression support new treatment strategies. This article explores the antiproliferative, proapoptotic and radiosensitizing effects of Methoxyamine (MX), a base excision repair (BER) inhibitor that has shown anticancer potential by sensitizing tumor cells to ionizing radiation and chemotherapy. The DAOY (a desmoplastic cerebellar-derived MB) and ONS-76 (classical MB) cell lines were treated with MX at different concentrations, either alone or combined with various chemotherapeutic compounds: cisplatin (CDDP), temozolomide (TMZ) and thiotepa (THIO). Additionally, cell lines were exposed to MX and treated at different ionizing radiation fractions. Measurement of cell growth by XTT assay, clonogenic assay and detection of apoptotic cell death through caspase activity was obtained. Exposure to MX significantly decreased cell proliferation (p<0.05) while increasing cell apoptosis (p<0.05). Growth reduction was concentration-dependent for both DAOY and ONS-76 cells lines. Conversely, MX failed to enhance the cytotoxicity of CDDP, TMZ, and THIO. Moreover, MX treatment radiosensitized both cell lines, with ONS-76 cells being more prone to radiation effects at higher doses of exposure. These data support the role of MX as a direct cytotoxic compound for pediatric MB cells by inhibiting the BER pathway. Nevertheless, an antagonism, rather than a synergic or additive effect of MX with different concentrations of CDDP, TMZ and THIO was observed. Likewise, the radiosensitizing effect on MB cell lines seems to depend on radiation doses and MB subtype. This information may be relevant for clinical study designs employing BER inhibitors for MB.

• Authors: Julia A Pezuk, Elvis T Valera, Lara E A Delsin, Carlos A Scrideli, Luiz G Tone, Maria S Brassesco
• Journal: Central nervous system agents in medicinal chemistry (Cent Nerv Syst Agents Med Chem) Vol. 16 Issue 1 Pg. 67-72 ( 2015) ISSN: 1875-6166 [Electronic] United Arab Emirates
• PMID: 26553097 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Alkylating
• Hydroxylamines
• Radiation-Sensitizing Agents
• Dacarbazine
• Thiotepa
• methoxyamine
• Caspases
• Cisplatin
• Temozolomide

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Agents, Alkylating (pharmacology)
• Apoptosis (drug effects, radiation effects)
• Caspases (analysis, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects, radiation effects)
• Cerebellar Neoplasms (drug therapy, pathology)
• Child
• Cisplatin (pharmacology)
• DNA Repair (drug effects)
• Dacarbazine (analogs & derivatives, pharmacology)
• Humans
• Hydroxylamines (pharmacology)
• Medulloblastoma (drug therapy, pathology)
• Radiation, Ionizing
• Radiation-Sensitizing Agents (pharmacology)
• Temozolomide
• Thiotepa (pharmacology)
• Tumor Stem Cell Assay