Your browser doesn't support javascript.
loading
MGMT-inhibitor in combination with TGF-ßRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells.
Das, A; Henderson, F C; Alshareef, M; Porto, G B F; Kanginakudru, I; Infinger, L K; Vandergrift, W A; Lindhorst, S M; Varma, A K; Patel, S J; Cachia, D.
Afiliación
  • Das A; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA. dasa@musc.edu.
  • Henderson FC; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Alshareef M; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Porto GBF; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Kanginakudru I; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Infinger LK; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Vandergrift WA; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Lindhorst SM; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Varma AK; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Patel SJ; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
  • Cachia D; Department of Neurosurgery (Divisions of Neuro-Oncology) and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina at Charleston, Charleston, SC, 29425, USA.
Clin Transl Oncol ; 23(3): 612-619, 2021 Mar.
Article en En | MEDLINE | ID: mdl-32710211
BACKGROUND: Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-ßRI inhibitor) seeking to overcome GB treatment resistance. METHODS: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. RESULTS: Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-ß-dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. CONCLUSION: This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Metilasas de Modificación del ADN / Glioblastoma / Antineoplásicos Alquilantes / Proteínas Supresoras de Tumor / Enzimas Reparadoras del ADN / Quinasa 4 Dependiente de la Ciclina / Quinasa 6 Dependiente de la Ciclina / Temozolomida / Receptor Tipo I de Factor de Crecimiento Transformador beta Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Clin Transl Oncol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Italia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Metilasas de Modificación del ADN / Glioblastoma / Antineoplásicos Alquilantes / Proteínas Supresoras de Tumor / Enzimas Reparadoras del ADN / Quinasa 4 Dependiente de la Ciclina / Quinasa 6 Dependiente de la Ciclina / Temozolomida / Receptor Tipo I de Factor de Crecimiento Transformador beta Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Clin Transl Oncol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Italia