Effects of statins and farnesyl transferase inhibitors on <scp>ERK</scp> phosphorylation, apoptosis and cell viability in non‐small lung cancer cells

Pelaia, Girolamo; Gallelli, Luca; Renda, Teresa; Fratto, D.; Falcone, Daniela; Caraglia, Michele; Busceti, Maria Teresa; Terracciano, Rosa; Vatrella, Alessandro; Maselli, Roberta; Savino, Rocco

doi:10.1111/j.1365-2184.2012.00846.x

Cited by 68 publications

(52 citation statements)

References 33 publications

(39 reference statements)

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“…Simvastatin has been used in combination therapy with several chemotherapeutic agents/targeted therapies such as farnesyl transferase inhibitors, EGFR inhibitors geftinib and cetuximab, doxorubicin, non-steroidal anti-inflammatory drugs, and vitamin-E gamma tocotrienol in diverse tumor cell lines and in vivo cancer models [10,13,16,[32][33][34] but so far its effects either alone or in combination with anticancer therapies in gastric cancer mouse models has never been studied before. Recently conducted couple of populationbased case-control studies clearly indicate that statins uptake can reduce the risk of gastric cancer [35], and our findings provide further scientific evidence that simvastatin has significant potential for the treatment of gastric cancer and its effects can be further enhanced by capecitabine.…”

Section: Discussionmentioning

confidence: 99%

“…The potential anti-carcinogenic effects of simvastatin alone or in combination with various anticancer therapies have been documented in a number of tumor cell lines and mouse models, including colorectal [10], hepatocellular [11], prostate [12], breast [13], and hematological malignancies [14]. How simvastatin exerts its anticancer effects is not fully understood, but it has been found to modulate various signaling cascades including mitogen-activated protein kinases [15,16], PI3-K/ Akt [17], NF-κB [18][19][20], STAT3 [14], cell cycle-dependent kinases [21], Rho-dependent kinase [22,23], and Ras-related C3 botulinum toxin substrate 1 [24].…”

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confidence: 99%

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Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

et al. 2013

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Chemoresistance remains a major problem in the treatment of gastric cancer patients. Hence, novel pharmacological agents that can overcome drug resistance are urgently required. Whether simvastatin can sensitize the gastric cancer to the antitumor effects of capecitabine in vitro and in vivo was investigated. The effect of simvastatin on the proliferation of gastric cancer cells was examined by mitochondrial dyeuptake 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis by esterase staining, NF-κB activation by DNA binding assay, and protein expression by western blot analysis. The effect of simvastatin on the tumor growth in xenograft mouse model of human gastric cancer was also examined. Simvastatin suppressed the proliferation of gastric cancer cells, enhanced the apoptotic effects of capecitabine, suppressed the constitutive activation of NF-κB, and abrogated the expression of cyclooxygenase-2 (COX-2), cyclin D1, Bcl-2, survivin, CXC motif receptor 4, and MMP-9 proteins. In a xenograft mouse model, we observed that the administration of simvastatin alone (5 mg/ kg body weight, intraperitoneal thrice/week) significantly suppressed the growth of the tumor and this effect was further potentiated by capecitabine treatment. As compared to the vehicle control, simvastatin also suppressed the expression of NF-κB-regulated gene products such as cyclin D1, COX-2, ICAM-1, MMP-9, survivin, Bcl-xL, and XIAP in tumor tissues. Overall, our results demonstrate that simvastatin can enhance the effects of capecitabine through suppression of NF-κB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

et al. 2013

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“…However, several new therapeutic strategies have been recently tested in model organisms [35][36][37][38], including lovastatin [1]. Previously, statins have been reported to decrease proliferation, survival, cell cycle progression, and migration in other cells including aggressive cancer models, amongst others by MAPK pathway inhibition [10,[25][26][27]29,30,[39][40][41]. However, currently evidence that statin treatment will be potent in the most aggressive type of PHEOs/PGLs, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The extent of the anti-cancer effects has been shown to vary depending on model and type of statin used [24][25][26][27][28][29][30]. Thus, we evaluated which of the seven currently available statins may be most effective for PHEO/PGL treatment.…”

Section: Introductionmentioning

confidence: 99%

Anti-cancer potential of MAPK pathway inhibition in paragangliomas – effect of different statins on mouse pheochromocytoma cells

Fliedner¹,

Engel²,

Lendvai³

et al. 2014

Exp Clin Endocrinol Diabetes

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To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT), which was accompanied by decreased phosphorylation of mitogen-activated kinase (MAPK) pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs/PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase (SDH) B mutation-derived PHEOs/PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread.

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“…The anticancer function of statins is based on preclinical evidence of their antiproliferative, pro-apoptotic and anti-angiogenic properties. A growing body of evidence suggests that various statins possess antiproliferative, anti-invasive, antimetastatic and pro-apoptotic properties in various types of cancer cell (11)(12)(13)(14). Simvastatin, one of the HMG-CoA reductase inhibitors, is currently used as a safe and well-tolerated therapeutic agent for the treatment of hypercholesterolemia, atherosclerosis and stroke (15).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism underlying the anticancer effect of simvastatin on MDA-MB-231 human breast cancer cells

Shen

Yuan²,

et al. 2012

Molecular Medicine Reports

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Abstract. Breast carcinoma is the leading cause of cancer-associated mortality in female individuals worldwide. Previous studies have investigated the pro-apoptotic and antimetastatic effects of statins, and have demonstrated that simvastatin exhibits antitumor activity and potent chemopreventive effects. However, the mechanism underlying the effects of simvastatin in breast cancer remains to be elucidated. The present study demonstrated that simvastatin inhibited the proliferation of MDA-MB-231 human breast cancer cells in a dose-dependent manner, decreased the protein expression of B cell lymphoma 2 (Bcl-2) and increased the protein expression of Bcl-2-associated X protein in timeand dose-dependent manners. In addition, simvastatin arrested cells in the G 0 /G 1 phase of the cell cycle, downregulated the protein expression levels of cyclin D1 and cyclin-dependent kinase (CDK)2, mediated the mitochondria-dependent caspase cascade by increasing the protein expression levels of caspase-3, -8 and -9, and downregulated the protein expression of X-linked inhibitor of apoptosis, which induced cell apoptosis. In addition, simvastatin decreased the protein expression of matrix metalloproteinase (MMP)-2 and suppressed the activation of nuclear factor (NF)-κB in the MDA-MB-231 cells. Taken together, these results demonstrated that the antitumor effect of simvastatin in the human MDA-MB-231 breast cancer cell line was via the inhibition of cell proliferation, affecting the cell cycle, downregulating the expression levels of cyclin D1 and CDKs, inducing apoptosis and decreasing the expression of MMP-2, possibly by inhibiting the activation of NF-κB. Statin treatment may provide a novel therapeutic approach for the treatment of breast cancer.

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Effects of statins and farnesyl transferase inhibitors on ERK phosphorylation, apoptosis and cell viability in non‐small lung cancer cells

Cited by 68 publications

References 33 publications

Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

Anti-cancer potential of MAPK pathway inhibition in paragangliomas – effect of different statins on mouse pheochromocytoma cells

Molecular mechanism underlying the anticancer effect of simvastatin on MDA-MB-231 human breast cancer cells

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