Pharmacological Targeting of the Integrated Protein Kinase B, Phosphatase and Tensin Homolog Deleted on Chromosome 10, and Transforming Growth Factor- Pathways in Prostate Cancer

Prostate cancer is a highly heterogenous disease in which a patient-tailored care program is much desired. Central to this goal is the development of novel targeted pharmacological interventions. To develop these treatment strategies, an understanding of the integration of cellular pathways involved in both tumorigenesis and tumor suppression is crucial. Of further interest are the events elicited by drug treatments that exploit the underlying molecular pathology in cancer. This review briefly describes the evidence that suggests integration of three established pathways: the tumorigenic phosphoinositide 3-kinase/protein kinase B (AKT) pathway, the tumor suppressive phosphatase and tensin homolog deleted on chromosome 10 pathway, and the tumor suppressive transforming growth factorpathway. More importantly, we discuss novel pharmaceutical agents that target key points of integration in these three pathways. These new therapeutic strategies include the use of agents that target iron to inhibit proliferation via multiple mechanisms and suppression of AKT by cytosolic phospholipase A2inhibitors. Prostate cancer is the most commonly diagnosed noncutaneous cancer in men and is the second leading cause of death (Assinder and Nicholson, 2007). It is estimated that approximately 186,000 new cases of prostate cancer will be diagnosed in the United States during 2008, accounting for approximately 22,000 deaths (available from the American Cancer Society, http://www.cancer.org). Radical prostatectomy (surgical removal) is the most common treatment strategy for organ-confined tumors (Steineck et al., 2002). Although this procedure has a 10-year survival of 60%, surgery has a 2% mortality rate, 70% of patients develop erectile dysfunction, and 50% have urine leakage with 2 to 5% of patients being left incontinent (Steineck et al., 2002). The most common treatment option for advanced metastatic prostate cancer is androgen deprivation either by surgical or chemical castration. However, in the majority of patients, the cancer becomes insensitive to androgen deprivation, leading to relapse, and they inevitably die from androgen-independent metastatic prostate cancer (Hussain and Dawson, 2000). Thus, improved treatment options are desperately needed. The work was supported by the National Health and Medical Research Council [Grant 400939] of Australia and the Australian Research Council [Grant DP0773027]. Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.108.053066. ABBREVIATIONS: PI3K/AKT, phosphoinositide 3-kinase/protein kinase B; AA, arachidonic acid; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; DFO, desferrioxamine; Dp44mT, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; GSK3 , glycogen synthase kinase 3 ; HIF-1 , hypoxia inducible factor-1 ; LOX, lipooxygenase; mTOR, mammalian target of rapamycin; NDRG1, N-myc downstream regulated gene-1; PIP3, phosphatidylinositol-3,4,5-triphosphate; PLA2, phospholipase A2; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RR, ribonucleotide reductase; Tf, transferrin; TfR1, transferrin receptor 1; TGF, transforming growth factor; TGFRI, transforming growth factorreceptor I; BpT, 2-benzoylpyridine thiosemicarbazone; PIP2, phosphatidylinositol-4,5-bisphosphate; PGE2, prostaglandin E2; EGR-1, early growth response gene; siRNA, small interfering RNA; MK886, 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid; 311, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone. 0026-895X/09/7503-429–436$20.00 MOLECULAR PHARMACOLOGY Vol. 75, No. 3 Copyright © 2009 The American Society for Pharmacology and Experimental Therapeutics 53066/3437809 Mol Pharmacol 75:429–436, 2009 Printed in U.S.A. 429 at A PE T Jornals on A ril 3, 2017 m oharm .aspeurnals.org D ow nladed from Key to developing improved pharmacological interventions for prostate cancer is an understanding of the integration of pathways known to be involved in the pathophysiology of prostate cancer. This review 1) briefly describes the tumorigenic phosphoinositide 3-kinase/protein kinase B (P13K/ AKT) pathway, the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and transforming growth factor (TGF) tumor suppressive pathways; 2) examines current evidence for the integration at key points of these pathways; and 3) discusses novel pharmaceutical agents that target these key points. Biochemical Pathways Known to Play a Role in Prostate