Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy
Abstract
The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways—or increase the activity of pathways that oppose them—with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators—of limited utility when administered individually—can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-κB, hypoxia-inducible factor-1α, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-β, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.
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Synergistic effect of curcumin on epigallocatechin gallate-induced ant...
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A comparison of plasma and prostate lycopene in response to typical se...
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Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implic...
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Erratum to “Inflammation and Its Role in Prostate Cancer” [Journal of ...
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Apigenin inhibits TGF-β-induced VEGF expression in human prostate carc...
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miR-Synth: a computational resource for the design of multi-site multi...
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Evaluation of 12-Lipoxygenase (12-LOX) and Plasminogen Activator Inhib...
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Inflammation and Its Role in Prostate Cancer
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Combination of Selenium and Green Tea Improves the Efficacy of Chemopr...
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Evidence for a Pro-Proliferative Feedback Loop in Prostate Cancer: The...
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Pharmacoproteomic Study of the Natural Product Ebenfuran III in DU-145...
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Toward Development of Novel Peptide-Based Cancer Therapeutics: Computa...
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Attenuation of Multifocal Cell Survival Signaling by Bioactive Phytoch...
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NF-kappaB2/p52 in Prostate Cancer
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p53 Regulates insulin-like growth factor-I receptor gene expression in...
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The Role of Vitamin D in Cancer Prevention and Treatment
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Evidence-based Anticancer Materia Medica for Prostate Cancer
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Curcumin enhances dasatinib‐induced inhibition of growth and transform...
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Anti-inflammatory Activity of Calcitriol in Cancer
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An Overview of Anticancer Herbal Medicines
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Microsomal prostaglandin E synthase‐1 and 5‐lipoxygenase: potential dr...
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The Role of Vitamin D in Cancer Prevention and Treatment
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Targeting anoikis resistance in prostate cancer metastasis
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Anti-inflammatory Activity of Calcitriol That Contributes to Its Thera...
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Microsomal prostaglandin E synthase 1 determines tumor growth in vivo ...
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Involvement of Both Extrinsic and Intrinsic Apoptotic Pathways in Apop...
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Curcumin Synergizes With Resveratrol to Inhibit Colon Cancer
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Dasatinib inhibits the growth of prostate cancer in bone and provides ...
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Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prost...
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Effects of Selenite and Genistein on G 2 /...
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Lupeol inhibits proliferation of human prostate cancer cells by target...
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Hypoxia increases normal prostate epithelial cell resistance to recept...
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A cross-talk between the androgen receptor and the epidermal growth fa...
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Diets high in selenium and isoflavones decrease androgen-regulated gen...
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Timing of supplementation of selenium and isoflavones determines prost...
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Mechanisms of selenium chemoprevention and therapy in prostate cancer
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cGMP‐independent anti‐tumour actions of the inhibitor of soluble guany...
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Pharmacokinetics, Pharmacodynamics and Drug Metabolism
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Prostaglandin E2 Regulates Tumor Angiogenesis in Prostate Cancer
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Regulation of Signaling Pathways by Selenium in Cancer
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Pilot Study of Rapamycin in Patients with Hormone-Refractory Prostate ...
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Search for Potential Markers for Prostate Cancer Diagnosis, Prognosis ...
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RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and...
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Isoflavones and the prevention of breast and prostate cancer: new pers...
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Development of Novobiocin Analogues That Manifest Anti-proliferative A...
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Curcumin enhances the effects of 5‐fluorouracil and oxaliplatin in med...
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Estrogen receptor activation and estrogen-regulated gene expression ar...
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The role of Src in prostate cancer
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Inhibition of Nuclear Factor-κB DNA Binding by Organoselenocyanates th...
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Regulation of Cox-2 by Cyclic AMP Response Element Binding Protein in ...
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Proteome‐wide changes induced by the Hsp90 inhibitor, geldanamycin in ...
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Lycopene and Lutein Inhibit Proliferation in Rat Prostate Carcinoma Ce...
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Delivering multiple anticancer peptides as a single prodrug using lysy...
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YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution ...
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Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel...
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Vasoactive intestinal peptide induces cyclooxygenase-2 expression thro...
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Combined Inhibitory Effects of Green Tea Polyphenols and Selective Cyc...
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Nutritional Interactions: Credentialing of Molecular Targets for Cance...
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The central role of osteoblasts in the metastasis of prostate cancer
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Role of Type 2C Protein Phosphatases in Growth Regulation and in Cellu...
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Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth fa...
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Molecular modeling of the non-covalent binding of the dietary tomato c...
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The tumor microenvironment in the post-PAGET era
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Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activ...
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An androgen-independent androgen receptor function protects from inosi...
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Epidermal Growth Factor Protects Prostate Cancer Cells from Apoptosis ...
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Constructing biological networks through combined literature mining an...
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Regulatory processes affecting androgen receptor expression, stability...
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The Crucial Role of Cyclooxygenase-2 in Osteopontin-Induced Protein Ki...
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Mechanisms of Curcumin- and EGF-Receptor Related Protein (ERRP)-Depend...
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A Computational Framework for the Topological Analysis and Targeted Di...
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The vitamin D analogue BXL-628 inhibits growth factor-stimulated proli...
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Insulin-Like Growth Factor (IGF) family and prostate cancer
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Complementary and Alternative Medicine for Advanced Prostate Cancer
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Mechanisms Underlying the Development of Androgen-Independent Prostate...
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Apoptosis evasion: The role of survival pathways in prostate cancer pr...
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Targeting NF-κB in Anticancer Adjunctive Chemotherapy
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Anoikis and Survival Connections in the Tumor Microenvironment: Is The...
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Multifocal Angiostatic Therapy: An Update
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Pathogenesis and Treatment of Prostate Cancer Bone Metastases: Targeti...
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Current strategies for the development of peptide‐based anti‐cancer th...
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YC-1 suppresses constitutive nuclear factor-κB activation and induces ...
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Morphoproteomics: exposing protein circuitries in tumors to identify p...
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