Potentiated antitumor effects of the combination treatment with statins and pamidronate in vitro and in vivo

Issat, Tadeusz; Nowis, Dominika; Legat, Magdalena; Makowski, Marcin; Klejman, Marcin P.; Urbański, Jakub; Skierski, Janusz; Koronkiewicz, Mirosława; Stokłosa, Tomasz; Brzezińska, Agnieszka; Bil, Jacek; Gietka, J; Jakóbisiak, Marek; Gołąb, Jakub

doi:10.3892/ijo.30.6.1413

Cited by 19 publications

(29 citation statements)

References 44 publications

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“…Statins were previously reported to enhance the effect of anticancer drugs and radiation therapy in other cancer cells, such as prostatic and pancreatic cancer cells (38)(39)(40), and the results of this study demonstrated that statins combined with anticancer drugs such as gemcitabine, cisplatin and 5-FU enhanced their effects in cholangiocarcinoma cells (Fig. 5).…”

Section: Discussionmentioning

confidence: 52%

Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Kamigaki

2011

Int J Oncol

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Abstract. Given the poor prognosis for cholangiocarcinoma, new and effective treatments are urgently needed. HMG-CoA reductase inhibitors (statins) reportedly exert anticancer effects in a variety of diseases, but there have been no reports of these effects in cholangiocarcinoma. In this study, we investigated the utility of statins for cholangiocarcinoma treatment. Proliferation suppression by pitavastatin and atorvastatin was investigated in the human cholangiocarcinoma cell lines HuCCT1 and YSCCC while changes in the cell cycle and intracellular signals were examined by FACS and Western blotting, respectively. Additive proliferation suppression by statins and pre-existing anticancer drugs was also investigated. HuCCT1 and YSCCC cell proliferation was dramatically suppressed by incubation with statins for 72 h or longer. Cell cycle analysis revealed a reduction in the G2M fraction and an increase in the sub-G1 fraction in statin-treated cells, while Western blotting showed increased levels of cleaved caspase-3 and a reduction in p-ERK. Furthermore, statins in combination with gemcitabine, cisplatin and 5-FU showed additive proliferation suppression. In this study, treatment of human cholangiocarcinoma cells with statins induced apoptosis via suppression of the classical MAPK pathway. Together, these results suggest that statins may be a new cholangiocarcinoma treatment option that could potentially enhance the anticancer effect of pre-existing anticancer drugs.

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Section: Discussionmentioning

confidence: 52%

Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Kamigaki

2011

Int J Oncol

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“…The importance of isoprenoid synthesis and prenylation in pancreatic cancer growth was reinforced when lovastatin in combination with pamidronate, an inhibitor of FPP synthase, was demonstrated to inhibit farnesylation and geranylgeranylation, and to exhibit synergistic antitumor effects in vitro and in vivo (55). Furthermore, statins were shown to improve survival and reduce tumor burden in animal models of pancreatic cancer compared with controls at doses below the maximum recommended dose for humans (56).…”

Section: Mechanisms Of Action and Evidence Of Antitumor Effects Of Stmentioning

confidence: 99%

Statins and pancreatic cancer

et al. 2017

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Abstract. Pancreatic cancer remains among the most lethal cancers, despite ongoing advances in treatment for all stages of the disease. Disease prevention represents another opportunity to improve patient outcome, with metabolic syndrome and its components, such as diabetes, obesity and dyslipidemia, having been recognized as modifiable risk factors for pancreatic cancer. In addition, statins have been shown to potentially reduce pancreatic cancer risk and to improve survival in patients with a combination of metabolic syndrome and pancreatic cancer. Furthermore, preclinical studies have demonstrated that statins exhibit antitumor effects in pancreatic cancer cell lines in vitro and animal models in vivo, in addition to delaying the progression of pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma (PDAC) and inhibiting PDAC formation in conditional K-Ras mutant mice. The mechanisms by which statins produce anticancer effects remain poorly understood, although appear to involve inhibition of the mevalonate/cholesterol synthesis pathway, thus blocking the synthesis of intermediates important for prenylation and activation of the Ras/mitogen-activated protein kinase 1 signaling pathway. Furthermore, statins have been identified to modulate the phosphoinositide 3-kinase/Akt serine/threonine kinase 1 and inflammation signaling pathways, and to alter the expression of genes involved in lipid metabolism, which are important for PDAC growth and proliferation. In addition, statins have been demonstrated to exhibit further antitumor mechanisms in a number of other cancer types, which are beyond the scope of the present review. In the present review, current evidence highlighting the potential of statins as chemopreventive agents in pancreatic cancer is presented, and the antitumor mechanisms of statins elucidated thus far in this disease are discussed.

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“…Thus, fluvastatin was shown to enhance the antiproliferatory effect of gemcitabine in MIA PaCa-2 pancreatic cancer cells [5]. Besides their in vitro effects, statins have been shown to inhibit pancreatic tumor growth in vivo [3,5,7]. In a recent study performed on nude mice it was shown that different statins decreased the tumor growth of transplanted Capan-2 cells [7].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies show that statins inhibit growth of pancreatic cancer cell lines in vitro and sensitize them for cytostatic drugs [3][4][5][6]. Gemcitabine, which is presently used for the treatment of pancreatic cancer, is one of these drugs.…”

Section: Introductionmentioning

confidence: 99%

Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells

Mistafa

Stenius

2009

Biochemical Pharmacology

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To cite this version:Oras Mistafa, Ulla Stenius. Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells. Biochemical Pharmacology, Elsevier, 2009, 78 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 37A c c e p t e d M a n u s c r i p t Abbreviations: 3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, 5-fluorouracil (5-Fu), phosphatidylinositol 3-kinase (PI3K), glycogen synthase kinase 3 beta (GSK3β), small interference RNA (siRNA), phosphorylation of Akt on residue Ser473 (pAkt Ser473), phosphorylation of Akt on residue Thr308 (pAkt Thr308), GSK3 on residue Ser9 (pGSK3β Ser9), nuclear factor kappa-B-(NF-B), mitogen-activated protein kinas (MAPK), Purinergic receptor (P2X), ligand-gated ion channel 7 (P2X7), Human embryonic kidney (HEK), adenosine 5′-triphosphate periodate oxidized sodium salt (o-ATP), Poly (ADP-ribose) polymerase (PARP).Key words: atorvastatin, P2X7, Akt, chemotherapy, pancreatic cancer * ManuscriptPage 2 of 37 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Thus, experiments employing P2X7 siRNA and inhibitors supported an involvement of P2X7. In Capan-2 cells, which expressed P2X7 in low levels, statins did not reduce pAkt levels nor did statins sensitize them to cytostatic drugs. However, statin inhibited the growth of Capan-2 cells and this correlated to inhibition of NFB and Raf/MEK pathways. As shown previously, these latter effects can be explained by an inhibited protein prenylation. Our data suggest that statins primarily target a functional P2X7-Akt signaling in pancreatic cancer cells. By targeting the P2X7-Akt axis, statins can sensitize pancreatic cancer cells to chemotherapeutic drugs. Our data are also in line with a role for P2X7 in the chemopreventive effect of statins on pancreatic cancer.

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Potentiated antitumor effects of the combination treatment with statins and pamidronate in vitro and in vivo

Cited by 19 publications

References 44 publications

Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells

Statins and pancreatic cancer

Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells

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