Candido Saverio, Abrams Stephen L, Steelman Linda, Lertpiriyapong Kvin, Martelli Alberto M, Cocco Lucio, Ratti Stefano, Follo Matilde Y, Murata Ramiro M, Rosalen Pedro L, Lombardi Paolo, Montalto Giuseppe, Cervello Melchiorre, Gizak Agnieszka, Rakus Dariusz, Suh Pann-Gill, Libra Massimo, McCubrey James A
Department of Biomedical and Biotechnological Sciences - Pathology & Oncology Section, University of Catania, Catania, Italy.
Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Adv Biol Regul. 2018 May;68:13-30. doi: 10.1016/j.jbior.2018.02.002. Epub 2018 Feb 12.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction of autophagy. In the following studies, we have examined the effects of metformin in the presence of various chemotherapeutic drugs, signal transduction inhibitors and natural products on the growth of three different PDAC lines. Metformin, by itself, was not effective at suppressing growth of the pancreatic cancer cell lines at concentration less than 1000 nM, however, in certain PDAC lines, a suboptimal dose of metformin (250 nM) potentiated the effects of various chemotherapeutic drugs used to treat pancreatic cancer (e.g., gemcitabine, cisplatin, 5-fluorouracil) and other cancer types (e.g., doxorubicin, docetaxel). Furthermore, metformin could increase anti-proliferative effects of mTORC1 and PI3K/mTOR inhibitors as well as natural products such as berberine and the anti-malarial drug chloroquine in certain PDAC lines. Thus, metformin can enhance the effects of certain drugs and signal transduction inhibitors which are used to treat pancreatic and various other cancers.
胰腺导管腺癌（PDAC）是一种侵袭性强、转移性高的恶性肿瘤，占胰腺癌的85%。PDAC患者预后较差，诊断和治疗后的五年生存率仅为5-10%。胰腺癌与II型糖尿病有关，因为与非糖尿病患者相比，近期诊断出的糖尿病患者在糖尿病初诊后10年内患胰腺癌的频率有所增加。二甲双胍是一种非常常用的治疗II型糖尿病的药物。二甲双胍部分通过刺激AMP激酶（AMPK）发挥作用，导致mTORC1活性受到抑制并诱导自噬。在以下研究中，我们研究了在存在各种化疗药物、信号转导抑制剂和天然产物的情况下，二甲双胍对三种不同PDAC细胞系生长的影响。二甲双胍本身在浓度低于1000 nM时对抑制胰腺癌细胞系的生长无效，然而，在某些PDAC细胞系中，次优剂量的二甲双胍（250 nM）增强了用于治疗胰腺癌（如吉西他滨、顺铂、5-氟尿嘧啶）和其他癌症类型（如阿霉素、多西他赛）的各种化疗药物的作用。此外，在某些PDAC细胞系中，二甲双胍可以增强mTORC1和PI3K/mTOR抑制剂以及小檗碱和抗疟药物氯喹等天然产物的抗增殖作用。因此，二甲双胍可以增强某些用于治疗胰腺癌和其他各种癌症的药物及信号转导抑制剂的作用。
