The effects of metformin and simvastatin on the growth of LNCaP and RWPE-1 prostate epithelial cell lines

Pennanen, Pasi; Syvälä, Heimo; Bläuer, Merja; Savinainen, Kimmo; Ylikomi, Timo; Tammela, Teuvo L.J.; Murtola, Teemu J.

doi:10.1016/j.ejphar.2016.06.036

Cited by 22 publications

(20 citation statements)

References 34 publications

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“…Recent studies showed that metformin in combination with simvastatin induced G1-phase cell cycle arrest, and Ripk1-and Ripk3-dependent necrosis in prostate cancer cells. 38,39) The combination of metformin and simvastatin was found to decrease the levels of phospho-Akt and phospho-AMPKα1/α2. 40) The inhibitory effect and mechanisms of metformin in combination with atorvastatin have previously not been reported.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo

Wang

Huang

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphorextracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.Key words prostate cancer; atorvastatin; metformin; apoptosis; combination Prostate cancer is one of the common types of malignant disease in males in the world and is the second leading cause of cancer-related death in the United States. The American Cancer Society estimates for 2016 approximately 180890 new cases will be diagnosed and 26120 men will die of the disease, accounting for about 8.3% of male cancer-related deaths. 1)Androgen deprivation therapy is an effective treatment for advanced prostate cancer. Unfortunately, almost all patients treated with androgen deprivation therapy will progress to castration-resistant prostate cancer (CRPC).2,3) Docetaxel is the most commonly prescribed first-line chemotherapy for CRPC. 4) Although docetaxel provides a modest (2.4-month) increase in median overall survival, many patients with CRPC cannot tolerate this cytotoxic chemotherapy due to advanced age, medical comorbidities, or limited bone marrow reserves. 5)Therefore, the identification of an effective alternative therapy with less toxicity may lead to increased survival and an improved QOL.Metformin is a well-established agent for the treatment of type II diabetes. In addition to its efficacy in lowering glucose levels, recent reports indicate it may have antitumor effects in various cancers, including prostate cancer. 6) Diabetic patients receiving metformin have been shown to have a reduced cancer incidence and a decrease in cancer-specific mortality.7) Further, epidemiologic evidence revealed a decreased incidence of prostate cancer in men taking metformin, 8,9) and both animal and in vitro models demonstrate its activity in prostate cancer cell lines. 10,11) Finall...

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Section: Discussionmentioning

confidence: 99%

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo

Wang

Huang

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Through the utilization of these normal prostate cell lines, a greater understanding of the epithelial markers of PCa and the biological alterations leading up to PCa have been understood. Furthermore, these normal prostate cell lines have been instrumental in comparative studies using several drugs and compounds in assessing their carcinogenic/inhibitory roles in PCa . There is a greater need for more normal cell lines to understand the multistep progression of carcinogenesis, especially if we are to understand the reasons underlying the higher incidence and mortality rates of PCa in MAA …”

Section: Causes For Prostate Cancer Disparitiesmentioning

confidence: 99%

“…55 It then begs the question as to why is there not a greater PCa. 62,63 There is a greater need for more normal cell lines to understand the multistep progression of carcinogenesis, especially if we are to understand the reasons underlying the higher incidence and mortality rates of PCa in MAA. 64,65 Since the emergence of "omics," this has triggered an advent of target-specific treatment options for cancers as opposed to traditional chemotherapy.…”

Section: Transatlantic Trade In Africansmentioning

confidence: 99%

Disparities in prostate cancer incidence and mortality rates: Solvable or not?

et al. 2019

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Prostate cancer (PCa) is recognized as a disease possessing not only great variation in its geographic and racial distribution but also tremendous variation in its potential to cause morbidity and death and it, therefore, ought not to be considered a homogenous disease entity. Morbidity and death from PCa are disproportionately higher in men of African ancestry (MAA) who are generally observed to have more aggressive disease and worse outcomes following treatment compared to men of European ancestry (MEA). The higher rates of PCa among MAA relative to MEA appear to be multifactorial and related to inherent differences in biological aggressiveness; a continued lack of awareness of the disease and methods of prevention; a lower prevalence of screen‐detected PCa; comparatively lower access to quality healthcare as well as systemic and institutionalized disparities in the administration of optimal care to MAA in developed countries such as the United States of America where high‐quality care is available. Even when access to quality healthcare is assured in equal access settings, it appears that MAA still have worse outcomes after PCa treatment stage‐for‐stage and grade‐for‐grade compared to MEA, suggesting that, inherent racial, ethnic and biological differences are paramount in predicting poor outcomes. This review has explored the different contributing factors to the current disparities in PCa incidence and mortality rates with emphasis on the incongruence in how research has been conducted in understanding the disease towards developing therapies.

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“…In vitro, metformin has been shown to reduce proliferation in and growth of PCa cell lines such as LNCaP, PC3, and C4-2 cells [205,[288][289][290][291][292][293][294][295]. On the other hand, as a reflection of normal cellular machinery in non-malignant cells, metformin doses of up to 100mM does not appear to affect the proliferation of benign cells such as RWPE-1 [286].…”

Section: Metformin and Pca Cellsmentioning

confidence: 99%

“…Whilst several authors have published the ability of metformin to induce either apoptosis, autophagy or both, it is currently unknown the effects of metformin in castrate conditions supplemented with physiologically relevant doses of insulin [288,289,291,300,312,313]. It is in this knowledge void (supplemented by clinical data) that this thesis will explore some of the known pathways related to metformin that may assess the clinical implications of insulin induced treatment resistance.…”

Section: Metformin and Apoptosis/autophagymentioning

confidence: 99%

Androgen Deprivation Therapy (ADT), Metabolic Syndrome and Metastatic Prostate Cancer: In Vivo and In Vitro Assessments of Effects of Metformin

Rhee¹

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Research Title -In vivo In this translational research PhD project, we conducted a randomized, placebo-controlled clinical trial named ADT and Adjuvant Metformin (ADMET) trial to determine the metabolic and therapeutic effects of treating hyperinsulinaemia in men starting ADT using a diabetic medication called metformin. Men who had been diagnosed with metastatic PCa and commencing ADT as a standard strategy provided the opportunity to study the physiological and pathological impact of the acute rise in insulin levels resulting from the iatrogenic hypogonadism [6]. To assess for the therapeutic benefits of metformin, we used a variety of novel technologies such as circulating tumour cell (CTC) enumeration, culture, transcriptomic analysis, and molecular imaging.The clinical trial was commenced in September 2014 and was completed in March 2017. It concluded that hyperinsulinaemia and MS is a phenomenon that affects most patients when using ADT, although the changes can be ameliorated by metformin. The use of medication was associated with the reduced need for treatment of MS with agents such as statins and progression to CRPC. Further, the trial confirmed that insulin resistance at the time of starting treatment is associated with early development of CRPC and progression of the disease.Progression free survival was also demonstrated using a novel molecular imaging called Prostate Specific

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The effects of metformin and simvastatin on the growth of LNCaP and RWPE-1 prostate epithelial cell lines

Cited by 22 publications

References 34 publications

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Disparities in prostate cancer incidence and mortality rates: Solvable or not?

Androgen Deprivation Therapy (ADT), Metabolic Syndrome and Metastatic Prostate Cancer: In Vivo and In Vitro Assessments of Effects of Metformin

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