Samith Thomas Kochuparambil

Anticancer Efficacy of Simvastatin on Prostate Cancer Cells and Tumor Xenografts Is Associated with Inhibition of Akt and Reduced Prostate-Specific Antigen Expression

Prostate cancer is the second-leading cause of cancer-associated death among men in the United States. There has been renewed interest in the potential therapeutic benefits of statins for cancer. Simvastatin, a widely used generic drug for preventing cardiovascular events, is well known for its effects on cellular proliferation and inflammation, two key processes that also determine the rate of tumor growth. Although a growing body of evidence suggests that statins have the potential to reduce the risk of many cancers, there are discrepancies over the pro- and anticancer effects of statins. In the current study, we sought to investigate the effects of simvastatin on the Akt pathway in prostate cancer cells with respect to the regulation of various cell functions in vitro and tumor growth in vivo. Time- and dose-dependent effects of simvastatin on LNCaP (androgen-dependent) and PC3 (androgen-independent) cells indicate that treatment with simvastatin at concentrations as low as 25 μM was sufficient to inhibit serum-stimulated Akt activity. Akin to this, treatment with simvastatin significantly inhibited serum-induced cell migration, invasion, colony formation, and proliferation. Simvastatin-mediated effects on colony formation were rescued by adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in PC3 cell lines. A PC3 xenograft model performed in nude mice exhibited reduced tumor growth with simvastatin treatment associated with decreased Akt activity and reduced prostate-specific antigen (PSA) levels. Our findings demonstrate the therapeutic benefits of simvastatin for prostate cancer and suggest a link between simvastatin, regulation of Akt activity, and PSA expression in prostate tumors.

Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis

BackgroundRecent studies suggest the potential benefits of statins as anti-cancer agents. Mechanisms by which statins induce apoptosis in cancer cells are not clear. We previously showed that simvastatin inhibit prostate cancer cell functions and tumor growth. Molecular mechanisms by which simvastatin induce apoptosis in prostate cancer cells is not completely understood.MethodsEffect of simvastatin on PC3 cell apoptosis was compared with docetaxel using apoptosis, TUNEL and trypan blue viability assays. Protein expression of major candidates of the intrinsic pathway downstream of simvastatin-mediated Akt inactivation was analyzed. Gene arrays and western analysis of PC3 cells and tumor lysates were performed to identify the candidate genes mediating extrinsic apoptosis pathway by simvastatin.ResultsData indicated that simvastatin inhibited intrinsic cell survival pathway in PC3 cells by enhancing phosphorylation of Bad, reducing the protein expression of Bcl-2, Bcl-xL and cleaved caspases 9/3. Over-expression of PC3 cells with Bcl-2 or DN-caspase 9 did not rescue the simvastatin-induced apoptosis. Simvastatin treatment resulted in increased mRNA and protein expression of molecules such as TNF, Fas-L, Traf1 and cleaved caspase 8, major mediators of intrinsic apoptosis pathway and reduced protein levels of pro-survival genes Lhx4 and Nme5.ConclusionsOur study provides the first report that simvastatin simultaneously modulates intrinsic and extrinsic pathways in the regulation of prostate cancer cell apoptosis in vitro and in vivo, and render reasonable optimism that statins could become an attractive anti-cancer agent.

Comparable efficacy and lower cost of PBSC mobilization with intermediate-dose cyclophosphamide and G-CSF compared with plerixafor and G-CSF in patients with multiple myeloma treated with novel therapies

Studies comparing the efficacy and cost of stem cell mobilization with intermediate-dose CY (ID-CY) and G-CSF against plerixafor and G-CSF, specifically in multiple myeloma (MM) patients treated in the novel therapy era, are not available. Eighty-eight consecutive patients undergoing mobilization with ID-CY (3–4 g/m2) and G-CSF (n=55) were compared with patients receiving plerixafor and G-CSF (n=33). Compared with plerixafor, ID-CY use was associated with higher median peak peripheral blood CD34+ cell count (68 vs 160 cells/μL, P<0.001), and CD34+ cell yield on day 1 of collection (6.9 × 106 vs 11.7 × 106 cells/kg, P<0.001). Total CD34+ cell yield was significantly higher in the ID-CY patients (median collection 16.6 × 106 vs 11.6 × 106 cells/kg; P<0.001). ID-CY use was associated with significantly more frequent episodes of febrile neutropenia (16.3% vs 0%; P=0.02), intravenous antibiotic use (16.3% vs 3%; P=0.03) and hospitalizations (P=0.02). The average total cost of mobilization in the plerixafor group was significantly higher compared with the ID-CY group (

Impact of response to thalidomide-, lenalidomide- or bortezomib- containing induction therapy on the outcomes of multiple myeloma patients undergoing autologous transplantation

28 980 vs

Abstract B47: Pleiotropic effects of simvastatin on prostate tumor growth and metastasis

22 504.8; P=0.001). Our data indicate robust stem cell mobilization in MM patients treated with novel agents, with G-CSF and either ID-CY or plerixafor. When compared with plerixafor, ID-CY-containing mobilization was associated with significantly lower average total mobilization costs.

PI3 kinase integrates Akt and MAP kinase signaling pathways in the regulation of prostate cancer

Impact of response to thalidomide-, lenalidomide- or bortezomib- containing induction therapy on the outcomes of multiple myeloma patients undergoing autologous transplantation

410 ANTI-CANCER EFFICACY OF SIMVASTATIN ON PROSTATE CANCER CELLS AND TUMOR XENOGRAFTS IS MEDIATED THROUGH INHIBITION OF AKT

Background: Statins are a class of drugs that inhibits HMG-CoA reductase, a rate liming enzyme in cholesterol synthesis. Simvastatin, a widely used generic drug for preventing cardiovascular events inhibit inflammation and stabilize atherosclerotic plaques. Growing body of evidences suggest that statins have the potential to reduce the risk of many cancer types. Objectives and Hypothesis: Our long-term goal is to enable the development of new and innovative therapeutics for prostate cancer through better understanding of the molecular mechanisms regulating prostate cancer growth and bone metastasis. In prostate cancer cells, simvastatin is known to induce apoptosis. Akt, a multitask signaling molecule, is the major survival kinase activated in cancer cells. Our central hypothesis is that treatment with simvastatin will inhibit Akt affecting prostate cancer cell function, tumor growth and metastasis. The rationale for the proposed research is that, once it is known mechanistically how simvastatin regulates prostate cancer cell function, it is likely that prostate tumor growth and metastasis can be downregulated therapeutically utilizing simvastatin using a novel drug-repurposing strategy. This would be of singular importance in the management of this disease. Experimental Design and Results: In the current study, we sought to investigate the pleiotropic effects of simvastatin on major signaling pathways in prostate cancer cells with respect to the regulation of cellular functions such as migration, proliferation, colony/foci formation and invasion, along with its already known effects on apoptosis. Time- and dose-effects of simvastatin on LNCaP (androgen-dependent) and PC-3 (androgen-independent) cells indicated that treatment with as low as 25µM simvastatin was sufficient to inhibit serum-stimulated activation of Akt-mTOR and cRaf-ERK pathways. Akin to this, treatment with 25µM simvastatin significantly inhibited serum- and EGF-induced cell migration, invasion, colony formation and proliferation. Simvastatin-mediated effects on cell migration and colony formation was rescued by adenovirus-mediated expression of constitutively active Akt (myristoylated Akt) in androgen-independent prostate cancer cells lines such as PC3 and LnCAP C4-2. A xenograft model performed in nude mice exhibited reduced PC3 prostate tumor growth with simvastatin treatment (2mg/kg body weight/day for 2 weeks) demonstrating the therapeutic potential of simvastatin for prostate cancer therapy. Conclusions and Future Directions: Our findings suggest a link between simvastatin and Akt/ERK signaling in the regulation of prostate cancer growth and metastasis. Further investigation is currently underway in our laboratory to unravel the molecular mechanisms on simvastatin-mediated effects on prostate cancer leading to tumor growth and bone metastasis in vivo using transgenic mouse models such as AKt+ and TRAMP+ mice. We also plan to undertake a clinical study on patients with prostate cancer who were on statin treatment prior to and after diagnosis and analyze biopsy specimen from these patients. A prospective study will look at the role statins in prostate cancer prevention and/or on management. Our ultimate aim is to investigate if statins can be used as an adjuvant drug in the treatment of patients already diagnosed with prostate cancer. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B47.