期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 106, 期 2, 页码 E696-E710出版社
ENDOCRINE SOC
DOI: 10.1210/clinem/dgaa877
关键词
metformin; simvastatin; prostate cancer; androgen receptor; mTOR; cell-cycle inhibitors
资金
- Instituto de Salud Carlos III
- European Union (ERDF/ESF, Investing in your future) [PI16/00264, PI17/02287, CD16/00092]
- MINECO/MECD [PID2019-105564RB-I00, FPU16/06190, FPU17/00263, FPU18/02485, BFU2016-80360-R]
- Junta de Andalucia [BIO-0139]
- CIBERobn
- Nicolas Monardes Programme from the Servicio Andaluz de Salud, Junta de Andalucia, Spain [C1-0005-2019]
Prostate cancer is a major cause of cancer-related death globally among males. Research findings suggest that a combination therapy using biguanides and statins can potentially reduce tumor aggressiveness in prostate cancer patients. The study also highlights the strong anti-tumor effects of both types of medications on prostate cancer cells, with a more potent effect observed when they are combined.
Context Prostate cancer (PCa) is one of the leading causes of cancer-related death among the male population worldwide. Unfortunately, current medical treatments fail to prevent PCa progression in a high percentage of cases; therefore, new therapeutic tools to tackle PCa are urgently needed. Biguanides and statins have emerged as antitumor agents for several endocrine-related cancers. Objective To evaluate: (1) the putative in vivo association between metformin and/or statins treatment and key tumor and clinical parameters and (2) the direct effects of different biguanides (metformin/buformin/phenformin), statins (atorvastatin/simvastatin/lovastatin), and their combination, on key functional endpoints and associated signalling mechanisms. Methods An exploratory/observational retrospective cohort of patients with PCa (n = 75) was analyzed. Moreover, normal and tumor prostate cells (normal [RWPE-cells/primary prostate cell cultures]; tumor [LNCaP/22RV1/PC3/DU145 cell lines]) were used to measure proliferation/migration/tumorsphere-formation/signalling pathways. Results The combination of metformin+statins in vivo was associated to lower Gleason score and longer biochemical recurrence-free survival. Moreover, biguanides and statins exerted strong antitumor actions (ie, inhibition of proliferation/migration/tumorsphere formation) on PCa cells, and that their combination further decreased; in addition, these functional parameters compared with the individual treatments. These actions were mediated through modulation of key oncogenic and metabolic signalling pathways (ie, AR/mTOR/AMPK/AKT/ERK) and molecular mediators (MKI67/cMYC/androgen receptor/cell-cycle inhibitors). Conclusions Biguanides and statins significantly reduced tumor aggressiveness in PCa, with this effect being more potent (in vitro and in vivo) when both compounds are combined. Therefore, given the demonstrated clinical safety of biguanides and statins, our results suggest a potential therapeutic role of these compounds, especially their combination, for the treatment of PCa.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据