Lovastatin augments apoptosis induced by COX-2 selective inhibitors in colon cancer cells

Agarwal, Banke; Protiva, Petr; Swaroop, Prabhakar; Chuttani, Ram; Ramey, William G.; Holt, Peter R.

doi:10.1016/s0016-5085(00)84860-x

Cited by 108 publications

(152 citation statements)

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“…When investigated for the mechanism of this potentiation, we found the down-regulation of various antiapoptotic gene products, such as Bcl-2, Bclx L , cFLIP, IAP1, IAP2, and survivin by simvastatin. The downregulation of Bcl-2 by lovastatin has been reported previously (55). Like simvastatin, cycloheximide is also known to potentiate TNF-␣-induced apoptosis (56); however, cycloheximide mediates its effects through suppression of protein synthesis, whereas simvastatin mediates its effects through suppression of NF-B-regulated gene products as shown here.…”

Section: Discussionsupporting

confidence: 78%

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

Ahn

Sethi

Aggarwal

2007

The Journal of Immunology

101

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Numerous recent reports suggest that statins (hydroxy-3-methylglutaryl-CoA reductase inhibitors) exhibit potential to suppress tumorigenesis through a mechanism that is not fully understood. Therefore, in this article, we investigated the effects of simvastatin on TNF-α-induced cell signaling. We found that simvastatin potentiated the apoptosis induced by TNF-α as indicated by intracellular esterase activity, caspase activation, TUNEL, and annexin V staining. This effect of simvastatin correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1 and cyclooxygenase-2), cell survival (Bcl-2, Bcl-xL, cellular FLIP, inhibitor of apoptosis protein 1, inhibitor of apoptosis protein 2, and survivin), invasion (matrix mellatoproteinase-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor); all known to be regulated by the NF-κB. We found that simvastatin inhibited TNF-α-induced NF-κB activation, and l-mevalonate reversed the suppressive effect, indicating the role of hydroxy-3-methylglutaryl-CoA reductase. Simvastatin suppressed not only the inducible but also the constitutive NF-κB activation. Simvastatin inhibited TNF-α-induced IκBα kinase activation, which led to inhibition of IκBα phosphorylation and degradation, suppression of p65 phosphorylation, and translocation to the nucleus. NF-κB-dependent reporter gene expression induced by TNF-α, TNFR1, TNFR-associated death domain protein, TNFR-associated factor 2, TGF-β-activated kinase 1, receptor-interacting protein, NF-κB-inducing kinase, and IκB kinase β was abolished by simvastatin. Overall, our results provide novel insight into the role of simvastatin in potentially preventing and treating cancer through modulation of IκB kinase and NF-κB-regulated gene products.

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Section: Discussionsupporting

confidence: 78%

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

Ahn

Sethi

Aggarwal

2007

The Journal of Immunology

101

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“…Moreover, the in vivo simultaneous combination greatly inhibits human pancreatic tumours without any remarkable side effect on mice. At the present time, no association studies involving fluvastatin have been published yet; however, it has been previously shown that lovastatin enhanced the apoptosis induced by chemotherapeutic drugs, including 5-FU and cisplatin, in colon cancer cell lines (Agarwal et al, 1999). Furthermore, Holstein and Hohl (2001b) demonstrated synergism between paclitaxel and lovastatin on human cancer cell lines, whereas Feleszko et al (2002) showed an in vivo enhanced antitumour activity of doxorubicin in murine tumour models when associated with lovastatin.…”

Section: Discussionmentioning

confidence: 90%

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

et al. 2005

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The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5 0 -nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans.

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“…In vivo studies have revealed that statins can inhibit tumor cell growth, invasion and metasta sis [14][15][16]. In addition, statins sensitize cancer cells to che motherapy drugs [17][18][19]. Lovastatin treatment enhances the antitumor activity of doxorubicin, a common chemo therapeutic agent for a wide range of cancer [20].…”

Section: Introductionmentioning

confidence: 99%

Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression

Liu

Liang

Kumar

et al. 2008

Cancer Chemother Pharmacol

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Purpose Ovarian cancer is the leading cause of death among all gynecological malignancies in Western coun tries. Although therapy for ovarian cancer has been greatly improved in the past 20 years, the overall survival for patients with advanced ovarian cancer has not changed sig niWcantly. The poor survival rates in patients with advanced ovarian cancer are due both to late diagnosis and to lack of eVective drugs for the majority of patients who have a relapse and develop resistance to current chemotherapy agents used for ovarian cancer. Thus, developing and dis covering eVective novel drugs with diVerent molecular structures from conventional chemotherapy agents have become an urgent clinical need.

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Lovastatin augments apoptosis induced by COX-2 selective inhibitors in colon cancer cells

Cited by 108 publications

References 0 publications

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression

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