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References
Lim, W.T., et al, PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer. Oncol Rep, 2007. 17(4): 853–7.
Bahlis, N.J., et al, CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood, 2007. 109(11): 5002–10.
Govindarajan, B., et al, Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest, 2007. 117(3): 719–29.
Meng, Q., et al, Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal, 2006. 18(12): 2262–71.
Opel, D., et al, Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res, 2007. 67(2): 735–45.
Tazzari, P.L., et al, Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia, 2007. 21(3): 427–38.
Tokunaga, E., et al, Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer, 2006. 13(2): 137–44.
Uddin, S., et al, Role of phosphatidylinositol 3″-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood, 2006. 108(13): 4178–86.
Cantrell, DA., Phosphoinositide 3-kinase signalling pathways. J Cell Sci, 2001. 114(Pt 8): 1439–45.
Chang, F., et al, Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia, 2003. 17(3): 590–603.
Testa, J.R., et al and Bellacosa, A., AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA, 2001. 98(20): 10983–10985.
Carpten, J., et al, A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature, 2007. 448: 439–444.
Cheng, J.Q., Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Update, 5: 131–146.
Arlt, A., et al, Role of NF- βB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene, 2003. 22: 3242–3251.
Kneufermann, C., et al, HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene, 2003. 22: 3205–3512.
Yuan, Z.-Q., et al, AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: Implication of AKT2 in chemoresistance. J Biol Chem, 2003. 19: 2324–2330.
Nagata, Y., et al, PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell, 2004. 6: 117–127.
Athanassiadou, P., et al, The prognostic value of PTEN, p53, and beta-catenin in endometrial carcinoma: A prospective immunocytochemical study. Int J Gynecol Cancer, 2007. 17(3): 697–704.
Bepler, G., et al, RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol, 2004. 22(10): 1878–1885.
Edwards, L.A., et al, Inhibition of ILK in PTEN-mutant human glioblas-tomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene, 2005. 24(22): 3596–3605.
Ferraro, B., et al, EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer. J Clin Oncol, 2005. 23(9): 1921–1926.
Schmitz, M., et al, Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer, 2007. 120(6): 1284–92.
Sui, L., et al, Alteration and clinical relevance of PTEN expression and its correlation with survivin expression in epithelial ovarian tumors. Oncol Rep, 2006. 15(4): 773–8.
Tsutsui, S., et al, Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology, 2005. 68(4–6): 398–404.
Zhang, J., et al, Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway. Oncogene, 2003. 22(40): 6289–95.
Eng, C., PTEN: One gene, many syndromes. Hum Mutat, 2003. 22(3): 183–98.
Feng, Z., et al, The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res, 2007. 67(7): 3043–53.
Blanco-Aparicio, C., et al, PTEN, more than the AKT pathway. Carcinogenesis, 2007. 28(7): 1379–86.
Fruman, D.A., Meyers, R.E., and Cantley, L.C., Phosphoinositide kinases. Annu Rev Biochem, 1998. 67: 481–507.
Wymann, M.P., and Marone, R., Phosphoinositide 3-kinase in disease: Timing, location, and scaffolding. Current Opinion in Cell Biology, 2005. 17(2): 141–149.
Hunter, T., Signaling—2000 and beyond. Cell, 2000. 100(1): 113–27.
Datta, S.R., Brunet, A., and Greenberg, M.E., Cellular survival: a play in three Akts. Genes Dev, 1999. 13(22): 2905–27.
Hay, N., and Sonenberg, N., Upstream and downstream of mTOR. Genes Dev, 2004. 18(16): 1926–45.
Brunn, G.J., et al, Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J, 1996. 15(19): 5256–67.
Cho, D., et al, The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res, 2007. 13(2 Pt 2): 758s–763s.
Smolewski, P., Recent developments in targeting the mammalian target of rapamy-cin (mTOR) kinase pathway. Anticancer Drugs, 2006. 17(5): 487–94.
Sun, S.Y., Fu, H., and Khuri, F.R., Targeting mTOR signaling for lung cancer therapy. J Thorac Oncol, 2006. 1(2): 109–11.
Sun, S.Y., et al, Activation of Akt and eIF4E survival pathways by rapamycin-medi-ated mammalian target of rapamycin inhibition. Cancer Res, 2005. 65(16): 7052–8.
Hay, N., The Akt-mTOR tango and its relevance to cancer. Cancer Cell, 2005. 8(3): 179–83.
Franke, T.F., et al, PI3K/Akt and apoptosis: Size matters. Oncogene, 2003. 22(56): 8983–98.
Downward, J., PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol, 2004. 15(2): 177–82.
Liang, J., et al, PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med, 2002. 8(10): 1153–60.
Paik, J.H., et al, FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell, 2007. 128(2): 309–23.
Dong, X.Y., et al, FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res, 2006. 66(14): 6998–7006.
Mayo, L.D., and Donner, D.B., A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A, 2001. 98(20): 11598–603.
Mayo, L.D., et al, PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem, 2002. 277(7): 5484–9.
Zhou, M., et al, PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Cancer Res, 2003. 63(19): 6357–62.
Hino, S., et al, Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol Cell Biol, 2005. 25(20): 9063–72.
Cross, D.A., et al, Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 1995. 378(6559): 785–9.
Workman, P., Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett, 2004. 206(2): 149–157.
Fujita, N., et al, Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J Biol Chem, 2002. 277(12): 10346–53.
Basso, A.D., et al, Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. Oncogene, 2002. 21(8): 1159–66.
Hideshima, T., et al, Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene, 2001. 20(42): 5991–6000.
Tu, Y., Gardner, A., and Lichtenstein, A., The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: Roles in cytokine-dependent survival and proliferative responses. Cancer Res, 2000. 60(23): 6763–70.
Pene, F., et al, Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene, 2002. 21(43): 6587–97.
Yan, H., et al, Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res, 2006. 66(4): 2305–13.
Tai, Y.T., et al, CD40 induces human multiple myeloma cell migration via phosphati-dylinositol 3-kinase/AKT/NF-kappa B signaling. Blood, 2003. 101(7): 2762–9.
Descamps, G., et al, The magnitude of Akt/phosphatidylinositol 3″-kinase proliferating signaling is related to CD45 expression in human myeloma cells. J Immunol, 2004. 173(8): 4953–9.
Gomez-Manzano, C., et al, Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann Neurol, 2003. 53(1): 109–17.
Saito, Y., et al, Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells. Cancer Gene Ther, 2003. 10(11): 803–13.
Yi, H.-K., et al, Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells. Biochem Biophys Res Commun, 2005. 330(3): 760–767.
Hyun, T., et al, Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood, 2000. 96(10): 3560–8.
Garlich, J., Development of a vascular targeted pan-PI3K inhibitor for cancer therapy. 3rd Focused Meeting on P13K signalling and disease Bath, UK 6–8 November 2006.
Bezieau, S., et al, High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat, 2001. 18: 212–242.
Liu, P., et al, Activating mutations of N and K-Ras in multiple myeloma show different clinical associations: Analysis of the Eastern Cooperative Oncology Group phase III trial. Blood, 1996. 88: 2699–2706.
David, E., et al, The combination of farnesyl transferase inhibitor lonafarnib and the proteosome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood, 2005. 106: 4322–4329.
Zhu, K., Blood et al, 2005. 105: 4759–4766. Farnesyl transferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells.
Tai, Y.T., et al, Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood, 2007. 110: 1656–1663.
Hideshima, T., et al, Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood, 2003. 101: 703–705.
Hideshima, T., et al, p38 MAPK inhibition enhances PS-341 (bortezomib) induced cytotoxicity against multiple myeloma cells. Oncogene, 2004. 23: 8766–8776.
Wang, S., et al, Optimizing immunotherapy in multiple myeloma: Restoring the function of patients' monocyte derived dentritic cells by inhibiting p38 or activating MEK/ERK/MAPK and neutralizing IL-6 in progenitor cells. Blood, 2006. 108: 4071–4077.
Garlich, J.R., et al, A vascular targeted pan phosphoinositide 3-kinase inhibitor prodng, SF1126, with antitumor and antiangiogenic activity. Cancer Res, 2008 68(1): 206–15.
Ruiter, G.A., et al, Anti-cancer alkyl-lysophospholipids inhibit the phosphati-dylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs, 2003. 14(2): 167–73.
Giuliani, N., et al, Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis. Leukemia, 2004. 18(3): 628–35.
Ihle, N.T., et al, Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther, 2004. 3(7): 763–72.
Ohta, T., et al, Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models. Endocrinology, 2006. 147(4): 1761–9.
Fujiwara, Y., et al, Blockade of the phosphatidylinositol-3-kinase-Akt signaling pathway enhances the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated. Mol Cancer Ther, 2007. 6(3): 1133–42.
Catley, L., et al, Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model. Exp Hematol, 2007. 35(7): 1038–46.
Gajate, C., and Mollinedo, F., Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood, 2007. 109(2): 711–9.
Hideshima, T., et al, Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood, 2006. 107(10): 4053–62.
Richardson, P., et al, A Multicenter Phase II Study of perifosine (KRX-0401) alone and in combination with dexamethasone (Dex) for patients with relapsed or relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts, 2006. 108(11): Abstract 3582.
Dees, E.C., et al, A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res, 2005. 11(2 Pt 1): 664–71.
Sausville, E.A., et al, Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol, 2001. 19(8): 2319–33.
Dai, Y., Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation. Blood, 2007. 109(10): 4415–23.
Jiang, K., et al, The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol, 2000. 20(1): 139–48.
Yanamandra, N., et al, Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia. Clin Cancer Res, 2006. 12(2): 591–9.
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Harvey, R.D., Silberman, J., Lonial, S. (2008). The PI3 Kinase/Akt Pathway as a Therapeutic Target in Multiple Myeloma. In: Lonial, S. (eds) Myeloma Therapy. Contemporary Hematology. Humana Press. https://doi.org/10.1007/978-1-59745-564-0_20
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DOI: https://doi.org/10.1007/978-1-59745-564-0_20
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