Type 2 Diabetes in Neuroendocrine Tumors

Are Biguanides and Statins Part of the Solution?

Aura D. Herrera-Martínez; Sergio Pedraza-Arevalo; Fernando L-López; Manuel D. Gahete; María A. Gálvez-Moreno; Justo P. Castaño; Raúl M. Luque

Disclosures

J Clin Endocrinol Metab. 2019;104(1):57-73. 

In This Article

Abstract and Introduction

Abstract

Context: Biguanides and statins exert beneficial effects on various cancer types. Their precise effects and underlying molecular mechanisms are poorly understood.

Materials and Methods: We analyzed the relationship between metabolic syndrome and histological, epidemiological, and prognosis variables in two cohorts of patients with neuroendocrine tumors (NETs): those with lung carcinoids (LCs; n = 81) and those with gastroenteropancreatic NET (GEP-NET; n = 100). Biguanide and statin antitumor effects were investigated by evaluating proliferation, migration, secretion, gene expression, and involved molecular pathways in BON1/QGP1 cell cultures.

Results: Pleura invasion was higher (LCs group; P < 0.05) and tumor diameter tended to be increased (GEP-NET group) in patients with type 2 diabetes (T2DM) than in those without. Somatostatin and ghrelin systems mRNA levels differed in tumor tissue of patients with T2DM taking metformin or not. Biguanides decreased proliferation rate in BON1/QGP1 cells; the effects of statins on proliferation rate depended on the statin and cell types, and time. Specifically, only simvastatin and atorvastatin decreased proliferation in BON1 cells, whereas all statins decreased proliferation rate in QGP1 cells. Metformin and simvastatin decreased migration capacity in BON1 cells; biguanides decreased serotonin secretion in BON1 cells. Phenformin increased apoptosis in BON1/QGP1 cells; simvastatin increased apoptosis in QGP1 cells. These antitumor effects likely involved altered expression of key genes related to cancer aggressiveness.

Conclusion: A clear inhibitory effect of biguanides and statins was seen on NET-cell aggressiveness. Our results invite additional exploration of the potential therapeutic role of these drugs in treatment of patients with NETs.

Introduction

Biguanides comprise a class of drugs with relevant effects as insulin-sensitizing agents; consequently, they are used to treat type 2 diabetes (T2DM), a severe disease with distinct comorbidities and whose incidence, along with that of the associated metabolic syndrome and other concomitant diseases, is growing worldwide.[1] The inflammation and insulin resistance present in patients with T2DM or metabolic syndrome have been associated with increased incidence of neoplasms.[2] Thus, some treatment options targeting related pathways, as may be the case of biguanides, could be beneficial in some types of cancer. In this context, a putative specific relationship between T2DM–metabolic syndrome and neuroendocrine tumors (NETs) has not been established yet.

Among biguanides, only metformin is commercially available for medical use, because it has a safe profile and is well tolerated. Phenformin and buformin were withdrawn in the early 1970s because of an association with lactic acidosis and increased risk for cardiac death.[3,4] Interestingly, a putative association between metformin treatment and cancer prevention and treatment was suggested in 2005,[5] and multiple investigations have been published subsequently on this topic. Specifically, results of some epidemiological studies have suggested a decreased risk for pancreatic, liver, colon, lung, and breast cancers in patients with diabetes treated with metformin.[6–9] This protective effect of metformin for cancer also has been found in patients with diabetes, according to several meta-analyses.[9–11] Moreover, biguanides can inhibit cell proliferation in vitro in several cancer cell lines, including pancreatic and NET cells.[12,13] In terms of signaling, biguanides stimulate AMP-activated protein kinase (AMPK), reduce hepatic gluconeogenesis and glycogenolysis, and increase glucose uptake in the muscle.[14,15] AMPK activation also suppresses the mammalian target of rapamycin (mTOR) 1, which is a key regulator of proliferation in cancer cells. AMPK induces cell cycle arrest and reduces insulin and insulin like growth factor 1 signaling.[16,17] Metformin-mediated AMPK activation may also result in p53-mediated cell cycle arrest or apoptosis.[18,19] It has been also suggested that metformin could inhibit cell proliferation by G0/G1, G2/M, or S phase arrest.[20] However, metformin may also exert antineoplastic properties in an AMPK-independent manner.[21]

Statins are also commonly used drugs in the therapeutic arsenal for patients with metabolic syndrome or T2DM. Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, affecting the rate-limiting step in cholesterol synthesis, but they also exert other clinical effects related to immunomodulatory mechanisms in vascular diseases, autoimmune diseases, and organ transplantation.[22] In addition, statins also reduce bone marrow stimulation and exert antiproliferative effects on smooth muscle cells.[23–26] The antitumor mechanisms of statins may include induced cell-cycle arrest, apoptosis induction and activation of the signaling of c-Jun N-terminal kinases (JNKs), decreased invasion or metastasis capacity, and decreased MKI67 expression.[27–31] These antitumor effects have been described in several tumor types, including melanoma, colon cancer, and breast cancer.[30–33] Moreover, statins have been proposed as an useful treatment option to induce apoptosis and decrease proliferation in pheochromocytomas and paragangliomas;[34,35] to the best of our knowledge, however, studies with statins have not yet been reported in NETs.

Because antineoplastic therapy in advanced NETs is still unsatisfactory, novel drugs for tumor growth control are required, especially in progressive and hereditary NETs, which are characterized by early onset and multiple lesions.[12] Therefore, based on the potential association among T2DM, metabolic syndrome, and cancer, we explored this association in a well-characterized cohort of lung carcinoids (LCs) and gastroenteropancreatic NETs (GEP-NETs). In addition, we analyzed the use of antidiabetic drugs and statins in these cohorts and explored their putative relationship with clinical and histological characteristics. Finally, we also investigated the potential in vitro antitumoral effects of different biguanides (namely, metformin, buformin, and phenformin) and statins (namely, atorvastatin, lovastatin, rosuvastatin, and simvastatin) in two different NET-cell models: BON1 and QGP1 cell lines.

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