Abstract
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 factor-β pathway. 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 A2-α inhibitors.
Footnotes
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The work was supported by the National Health and Medical Research Council [Grant 400939] of Australia and the Australian Research Council [Grant DP0773027].
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ABBREVIATIONS: PI3K/AKT, phosphoinositide 3-kinase/protein kinase B; AA, arachidonic acid; COX, cyclooxygenase; cPLA2-α, cytosolic phospholipase A2-α; DFO, desferrioxamine; Dp44mT, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; GSK3β, glycogen synthase kinase 3β; HIF-1α, hypoxia inducible factor-1α; LOX, lipooxygenase; mTOR, mammalian target of rapamycin; NDRG1, N-myc downstream regulated gene-1; PIP3, phosphatidylinositol-3,4,5-triphosphate; PLA2-α, phospholipase A2-α; PTEN, phosphatase and tensin homolog deleted on chromosome 10; RR, ribonucleotide reductase; Tf, transferrin; TfR1, transferrin receptor 1; TGF-β, transforming growth factor-β; TGF-βRI, transforming growth factor-β receptor 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.
- Received October 26, 2008.
- Accepted December 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Targeting of the Integrated Protein Kinase B, Phosphatase and Tensin Homolog Deleted on Chromosome 10, and Transforming Growth Factor-β Pathways in Prostate Cancer
