ABSTRACT
OBJECTIVE: Tumor hypoxia is associated with a poorer prognosis in cancer patients and can diminish the efficacy of radiation therapy (RT). This study investigates the potential of metformin to enhance radiosensitivity in hypoxic cancer cells. METHODS: Preliminary experiments were conducted to validate the impact of hypoxia on radiation response. Reactive oxygen species (ROS) levels, cell migration, and cell death were assessed in hypoxic, radiated cells treated with metformin. Proteomic and ontological analyses were employed to identify molecular targets associated with the radiosensitizing effect of metformin. Proteomic and ontological findings were validated through patient samples and in vitro studies. RESULTS: Metformin amplified cell death, induced DNA fragmentation, decreased cell migration, and elevated ROS levels in hypoxic, radiated cells. Proteomic analyses revealed that GAPDH and TAGLN2 were identified as pivotal targets linked to the radiosensitizing effect of metformin. Oral cancer patients exhibited elevated levels of TAGLN2 and reduced levels of GAPDH. Metformin downregulated TAGLN2 and upregulated GAPDH in hypoxic, radiated cells. Additionally, metformin reduced levels of mutated p53. CONCLUSIONS: This study suggests that metformin can enhance radiosensitivity in hypoxic cells, operating through modulation of GAPDH and TAGLN2. Furthermore, metformin effectively reduces mutated p53 levels in radiated cells under hypoxic conditions.
Subject(s)
Carcinoma, Squamous Cell , Metformin , Mouth Neoplasms , Radiation-Sensitizing Agents , Humans , Metformin/pharmacology , Metformin/therapeutic use , Mouth Neoplasms/radiotherapy , Radiation-Sensitizing Agents/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Radiation Tolerance/drug effects , Reactive Oxygen Species/metabolism , Proteomics , Glyceraldehyde-3-Phosphate Dehydrogenases , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) , Cell Hypoxia/drug effects , Tumor Hypoxia/drug effectsABSTRACT
BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive brain tumor. Even with the advent of temozolomide, patient survival remains poor, with expected median survival around 1 year from diagnosis. Consequently, the relentless search for new therapeutic strategies able to increase patient outcome persists. 3-[(dodecylthiocarbonyl) methyl] glutarimide (DTCM-g) is a new anti-inflammatory compound that already showed antitumor effects. MATERIALS AND METHODS: Clonogenic survival, proliferation, apoptosis, cell cycle progression and invasion capacity of pediatric and adult GBM cell lines (U87MG, U251MG, SF188 and KNS-42) were evaluated under treatment with DTCM-g. The combined treatment with radiation was also evaluated in vitro and in vivo through xerographic models. RESULTS: DTCM-g is able to impair proliferation, reduce clonogenic capacity and induce cell cycle arrest in GBM cell lines. No alteration in apoptosis rates was found after treatment. DTCM-g also reduces the invasion capacity of all GBM cell lines without alterations in MMP2 and uPa expression. Moreover, the drug radiosensitized GBM in vitro and in vivo. CONCLUSION: Although additional studies are still necessary to support our findings, our results suggest that DTCM-g may be a promising drug on the adjuvant treatment of GBM exhibiting antitumor effects, especially through radiosensitization.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/therapy , Glioblastoma/therapy , Piperidones/therapeutic use , Radiation-Sensitizing Agents/therapeutic use , Animals , Apoptosis/drug effects , Apoptosis/radiation effects , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Cell Cycle/drug effects , Cell Cycle/radiation effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Combined Modality Therapy/methods , Glioblastoma/drug therapy , Glioblastoma/radiotherapy , Humans , Mice , Mice, Inbred BALB C , Mice, NudeABSTRACT
De acordo com dados do Instituto Nacional de Câncer do Brasil, quase 30% dos pacientes novos com câncer de mama apresentam no momento do diagnóstico, tumor localmente avançado, inoperável, sendo necessário tratamento primário com quimioterapia. Usualmente esquemas baseados em antraciclinas são efetivos, porém cerca de 30% dos tumores não responderão. Para estes pacientes ainda não existe uma segunda linha de tratamento estabelecida. Objetivo: Avaliar eficácia e toxicidade de radioterapia e capecitabina como segunda linha neo-adjuvante. Pacientes e Métodos: Vinte e oito pacientes com câncer de mama localmente avançados, refratários à quimioterapia primária com antraciclinas, foram estudados entre janeiro de 2003 e maio de 2004. Os pacientes receberam radioterapia (50Gy) e capecitabina (850mg/m2) duas vezes ao dia por 14 dias cada 3 semanas. Resultados: Vinte três de 28 pacientes (82%) tornaram se operáveis. Cinco pacientes não realizaram a cirurgia por progressão de doença. A mediana do tamanho do tumor por avaliação clínica reduziu de 80 cm² para 49cm². Doença residual microscópica foi observada em 3 pacientes (13%) e resposta patológica completa em um paciente. A mediana de linfonodos acometidos foi de dois. O tratamento foi bem tolerado, sem eventos grau 3 ou 4. Conclusão: Nossos resultados indicam que o tratamento de segunda linha neo-adjuvante com radioterapia e capecitabina em pacientes com câncer de mama localmente avançado e refratários a quimioterapia primária com antraciclinas, foi eficaz e bem tolerado. Estudo randomizado e prospectivo comparando radioterapia isolada e capecitabina combinada com radioterapia deverá ser realizado
According to data from Brazils National Cancer Institute, nearly 30% of the new patients who present with breast cancer have locally advanced disease. These patients are inoperable, and tumor reduction is usually attempted with chemotherapy. Firstline anthracyclin-based neoadjuvant chemotherapy is often effective, but about 30% of the patients fail. For those, there is yet no established second-line treatment. Objectives: We have studied the concomitant use of radiation therapy and capecitabine in this setting, in order to determine the toxicity and efficacy of this regimen as a second-line neoadjuvant treatment. Methods: Twenty-eight patients with inoperable locally advanced breast cancer refractory to first-line anthracycline based treatment were enrolled between January 2003 and May 2004. Patients received radiation therapy (50Gy) and concomitant capecitabine (850mg/m²) for 14 days every 3 weeks. Results: This treatment rendered 23 of the 28 patients (82%) operable. The five remaining patients did not undergo surgery due to disease progression. The median clinical tumor size decreased from 80 cm2 to 49 cm2. Microscopic residual disease was observed in 3 patients (13%), and another patient achieved a complete pathologic response. The median number of involved lymph nodes was two. Treatment was well tolerated, with no grade 3 or 4 events. Conclusion: Our data indicate that second-line neoadjuvant treatment with radiation therapy and capecitabine is feasible, well tolerated and effective in patients with locally advanced breast cancer refractory to primary anthracycline-based treatment. These results suggest that a randomized study should be done to compare radiotherapy alone to capecitabine combined with radiotherapy