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

Bocci G, Fioravanti A, Orlandi P, Bernardini N, Collecchi P, Del Tacca M, Danesi R - Br. J. Cancer (2005)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology and Chemotherapy, University of Pisa, Via Roma, I-56126 Pisa, Italy.

ABSTRACT
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'-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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(A) Chemotherapeutic effect of gemcitabine 120 mg kg−1 i.p. four times at 3-day intervals and fluvastatin 30 mg kg−1 i.p. every 2 days alone or in combination on MIAPaCa-2 tumours xenotransplanted in CD nu/nu mice. *P<0.05 with respect to controls; **P<0.05 vs gemcitabine and fluvastatin alone. Symbols and bars, mean±s.e. (B) Body weight of MIAPaCa-2 tumour-bearing control mice and mice treated with gemcitabine and fluvastatin alone or in combination. No changes or decline in body weight were noted. Symbols and bars, mean±s.e.
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fig10: (A) Chemotherapeutic effect of gemcitabine 120 mg kg−1 i.p. four times at 3-day intervals and fluvastatin 30 mg kg−1 i.p. every 2 days alone or in combination on MIAPaCa-2 tumours xenotransplanted in CD nu/nu mice. *P<0.05 with respect to controls; **P<0.05 vs gemcitabine and fluvastatin alone. Symbols and bars, mean±s.e. (B) Body weight of MIAPaCa-2 tumour-bearing control mice and mice treated with gemcitabine and fluvastatin alone or in combination. No changes or decline in body weight were noted. Symbols and bars, mean±s.e.

Mentions: MIAPaCa-2 cells injected s.c. in CD nu/nu mice grew quite rapidly and tumour masses became detectable 9 days after xenotransplantation. Tumours in control animals showed a progressive enlargement in their dimensions, and a mean volume of ∼550 mm3 was reached at the end of the experimental period (Figure 10A). Both fluvastatin and gemcitabine were able to inhibit tumour growth, although to different extents, and their therapeutic effect was significant starting on the 19th day after implant as compared to controls (Figure 10A). In the group of animals receiving the combined treatment with fluvastatin and gemcitabine, the reduction in tumour growth was significant already on day 19 with respect to controls (Figure 10A). The tumour growth curve of fluvastatin+gemcitabine showed a significant decrease during the 14-day schedule, divergent from that of controls, as well as from fluvastatin- and gemcitabine-treated animals, and at days 22 and 27 the tumour volume was significantly different from that of controls and of animals given fluvastatin and gemcitabine alone, respectively (Figure 10A). It is noteworthy that the combination of fluvastatin and gemcitabine resulted in an almost complete regression of tumour volumes (Figure 10A). Interestingly, all the drug schedules showed tumour relapses in all the treated groups at the end of the experiments, but with a significant delay in the case of the combination treatment. The toxicity profile was favourable and acceptable for both single and combination treatment, with no loss of weight throughout the course of the experiment (Figure 10B).


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

Bocci G, Fioravanti A, Orlandi P, Bernardini N, Collecchi P, Del Tacca M, Danesi R - Br. J. Cancer (2005)

(A) Chemotherapeutic effect of gemcitabine 120 mg kg−1 i.p. four times at 3-day intervals and fluvastatin 30 mg kg−1 i.p. every 2 days alone or in combination on MIAPaCa-2 tumours xenotransplanted in CD nu/nu mice. *P<0.05 with respect to controls; **P<0.05 vs gemcitabine and fluvastatin alone. Symbols and bars, mean±s.e. (B) Body weight of MIAPaCa-2 tumour-bearing control mice and mice treated with gemcitabine and fluvastatin alone or in combination. No changes or decline in body weight were noted. Symbols and bars, mean±s.e.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361561&req=5

fig10: (A) Chemotherapeutic effect of gemcitabine 120 mg kg−1 i.p. four times at 3-day intervals and fluvastatin 30 mg kg−1 i.p. every 2 days alone or in combination on MIAPaCa-2 tumours xenotransplanted in CD nu/nu mice. *P<0.05 with respect to controls; **P<0.05 vs gemcitabine and fluvastatin alone. Symbols and bars, mean±s.e. (B) Body weight of MIAPaCa-2 tumour-bearing control mice and mice treated with gemcitabine and fluvastatin alone or in combination. No changes or decline in body weight were noted. Symbols and bars, mean±s.e.
Mentions: MIAPaCa-2 cells injected s.c. in CD nu/nu mice grew quite rapidly and tumour masses became detectable 9 days after xenotransplantation. Tumours in control animals showed a progressive enlargement in their dimensions, and a mean volume of ∼550 mm3 was reached at the end of the experimental period (Figure 10A). Both fluvastatin and gemcitabine were able to inhibit tumour growth, although to different extents, and their therapeutic effect was significant starting on the 19th day after implant as compared to controls (Figure 10A). In the group of animals receiving the combined treatment with fluvastatin and gemcitabine, the reduction in tumour growth was significant already on day 19 with respect to controls (Figure 10A). The tumour growth curve of fluvastatin+gemcitabine showed a significant decrease during the 14-day schedule, divergent from that of controls, as well as from fluvastatin- and gemcitabine-treated animals, and at days 22 and 27 the tumour volume was significantly different from that of controls and of animals given fluvastatin and gemcitabine alone, respectively (Figure 10A). It is noteworthy that the combination of fluvastatin and gemcitabine resulted in an almost complete regression of tumour volumes (Figure 10A). Interestingly, all the drug schedules showed tumour relapses in all the treated groups at the end of the experiments, but with a significant delay in the case of the combination treatment. The toxicity profile was favourable and acceptable for both single and combination treatment, with no loss of weight throughout the course of the experiment (Figure 10B).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology and Chemotherapy, University of Pisa, Via Roma, I-56126 Pisa, Italy.

ABSTRACT
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'-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.

Show MeSH
Related in: MedlinePlus