Metformin may offer no protective effect in men undergoing external beam radiation therapy for prostate cancer

Autor: Arthur Shulkes, Weranja Ranasinghe, David Wetherell, Graham S. Baldwin, Shomik Sengupta, Oneel Patel, Damien M Bolton, Joseph Ischia, Scott Williams
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Oncology
medicine.medical_specialty
endocrine system diseases
Cell Survival
Urology
medicine.medical_treatment
Adenocarcinoma
Metastasis
Androgen deprivation therapy
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Risk Factors
Internal medicine
Diabetes mellitus
medicine
Humans
Hypoglycemic Agents
Treatment Failure
Neoplasm Metastasis
Survival analysis
Neoplasm Staging
business.industry
Prostatic Neoplasms
nutritional and metabolic diseases
Androgen Antagonists
Radiotherapy Dosage
Middle Aged
Prostate-Specific Antigen
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
Survival Analysis
Metformin
Radiation therapy
Oxidative Stress
Prostate-specific antigen
030104 developmental biology
Diabetes Mellitus
Type 2
030220 oncology & carcinogenesis
PC-3 Cells
Neoplasm Grading
business
medicine.drug
Zdroj: BJU International. 123:36-42
ISSN: 1464-4096
DOI: 10.1111/bju.14709
Popis: OBJECTIVES: To assess whether metformin reduces radio-resistance and increases survival in men undergoing external beam radiation therapy (EBRT) for prostate cancer (PCa), and to determine its effect on hypoxia inducible factor 1-α (HIF1α). PATIENTS AND METHODS: All patients treated with curative intent with EBRT for PCa at a major cancer centre between 2000 and 2007 were included in this study. The outcome measures of time to biochemical failure (BF), metastasis, PCa-specific mortality and overall survival (OS) were analysed in those taking metformin vs those not, using competing risk and Cox regression models. To determine metformin's effect on HIF1α expression and survival in vitro, PC3 cells with high basal HIF1α levels were subjected to increasing doses of metformin after H2 O2 -induced oxidative stress. RESULTS: A total of 2055 eligible cases, including 113 who were on metformin, were identified, with a median follow-up of 95.7 months. There were no differences in age, initial prostate-specific antigen level, Gleason score, T-stage, D'Amico risk class or duration of androgen deprivation therapy (ADT) between patients who were or were not on metformin. Treatment with metformin did not result in any apparent improvement in time to BF, time to metastasis detection or OS, but there was a 1.5-fold increase in PCa-specific deaths (P = 0.045) in patients on metformin and ADT when adjusted for cancer risk and comorbidities. When comparing patients on high-dose metformin (>1 g/d) with those on low-dose metformin (≤1 g), there was no difference in either time to metastases or time to BF. In vitro metformin at a high concentration of 100 μM did not reduce HIF1α expression, nor did metformin affect the PC3 cell survival when exposed to oxidative stress (H2 O2 ). CONCLUSIONS: No association was found between the use of metformin and time to metastasis detection, time to BF or OS in patients undergoing radiation therapy with or without ADT for PCa. In vitro, low therapeutic concentrations of metformin had no effect on HIF1α, and this observation could explain the conflicting evidence for the effectiveness of metformin in men undergoing EBRT for PCa. Higher, more toxic doses of metformin may be required to inhibit the mammalian target of rapamycin-HIF1α pathway in this patient group.
Databáze: OpenAIRE
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