A triple combination of atorvastatin, celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors

Abstract

Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.

Statins and pancreatic cancer risk in patients with chronic pancreatitis: A Danish nationwide population‐based cohort study

“…Although our findings agree with a previous meta-analysis that found no association between statin use and pancreatic cancer risk in healthy individuals, 6 they contrast with the substantial experimental evidence suggesting that statins inhibit pancreatic carcinogenesis. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] An explanation for this discrepancy may be that poor lifestyle choice such as excessive alcohol consumption, tobacco smoking or a high level of comorbidity, which is frequently seen in chronic pancreatitis patients, 40,41 may mitigate any potentially beneficial effect of statins. Furthermore, the potential anticancer effect of statins may differ according to statin solubility (i.e., lipophilic or hydrophilic), 42 which our study was not large enough to examine.…”

“…5 Furthermore, experimental studies suggest that statins can decrease pancreatic cancer risk by interfering with vital intracellular signaling pathways. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] A recently published Danish case-cohort study of approximately 4,800 chronic pancreatitis patients suggested that statin use was associated with an 80% reduction in pancreatic cancer risk. 24 Although a compelling finding, the study reported a crude null finding and the beneficial effect of statins was only evident in a propensity-score matched analysis of 339 statin users (7% of the total population).…”

Statins and pancreatic cancer

“…The ability of atorvastatin to inhibit PI3K/Akt, Ras/MAPK and NF-κB signaling may be dependent on the underexpression of P2X7, at least in human pancreatic cancer cells in vitro (59). Combined inhibition of HMG-CoA reductase, COX-2 and farnesyl transferase in human pancreatic cancer cell lines in vitro was observed to inhibit tumor growth and to produce a stronger decrease in pAkt and pERK1/2 levels compared with each agent alone (60). A summary of the antitumor mechanisms of statins in pancreatic cancer from existing evidence is shown in Fig.…”

TRAIL Mediated Signaling in Pancreatic Cancer

“…More importantly, intraperitoneally injected EpCAMxCD3 Bispecific antibody substantially inhibited tumor formation in xenografted mice (Groth et al, 2012). It has recently been shown that a multipronged approach, consisting of atorvastatin, celecoxib and tipifarnib considerably reduced growth of the tumors in SCID mice xenografted with pancreatic cancer cells (Ding et al, 2014). PARP inhibitor (Olaparib) and the pan-Bcl-2 inhibitor (Obatoclax) represented anti-tumor activity in xenografted mice .…”