Medicinal Chemistry - Volume 7, Issue 5, 2011

Molecular medicine is the future of 21st century patient management. Molecular imaging can play pivotal roles in disease diagnosis, treatment efficacy assessment, drug discovery, and the understanding of fundamental biology. Positron emission tomography (PET) has been used in the clinic for decades and 18F-FDG has become indispensible in many facets of patient management, such as cancer staging and treatment monitoring. A wide variety of PET tracers are now in clinical investigation and it is expected that several more PET tracers may gain the Food and Drug Administration (FDA) approval for various medical indications in the United States. Driven by the ever-increasing availability of preclinical/clinical PET scanners and radioisotopes, research on PET nuclides has flourished over the last decade. There are hundreds of isotopes that emit positron, which can potentially be developed into PET tracers. However, such potential to a large extent strongly depends on the availability of the radioisotopes. In addition, the development of new imaging probes for PET is far from trivial and radiochemistry is a major limiting factor of the field. Therefore, this special issue of Medicinal Chemistry is solely focused on the radiochemistry for PET. Because of the excellent decay characteristics and a half-life of 110 minutes, 18F is the most widely used PET isotope in the clinic. In the first article of this issue, Dr. Zeng and co-workers gave a comprehensive overview on 18F radiochemistry, where various strategies and recent developments in 18F-labeling were summarized in great detail. Issues related to the production of 18F-based PET tracers for widespread use are also discussed. Next, Dr. Velikyan provided a thorough review on 68Ga (t1/2: 68.3 min), focusing on the achievements in chemistry as well as the diversity and potential of the resulting tracers. Recently, utilization of 68Ga has gained tremendous momentum and the development of new 68Ga-based imaging agents for targeted, pretargeted, non-targeted imaging and their clinical applications is increasing worldwide. Dr. Brechbiel and co-workers discussed in depth about the utility of 86Y (t1/2: 14.7 h), which can be imaged with PET and used as an isotopically matched surrogate radionuclide for evaluating the dosimetry of the corresponding therapeutic agent that is labeled with 90Y. This review discusses various aspects involved in the development of 86Y-based PET tracers with a specific emphasis on the radiochemistry and biological applications with antibodies and peptides. In the next review, Dr. Nickles and co-workers summarized the recent advances on 89Zr (t1/2: 3.3 d), an ideal radionuclide for use in PET imaging with monoclonal antibodies. The cyclotron physics of 89Zr production, chemical separation methods for isolating 89Zr from the yttrium target, as well as detailed procedures for the syntheses of 89Zr-labeled antibodies, were all included. The article by Dr. Divgi and co-workers is an excellent summary on 124I, which has a physical half-life of 4.2 d. The progress to date on the potential of 124I as a PET isotope, the production of 124I, as well as the radiochemistry to synthesize 124Ilabeled compounds (e.g. small molecules, peptides, proteins, and nanoparticles) were all discussed in exquisite detail. In addition, promising future directions in 124I-based PET radiochemistry and molecular imaging were also pointed out. Lastly, Dr. Wadas and co-workers provided a detail-oriented and thorough overview on the current status of radiopharmaceuticals based on copper radionuclides, which include 60Cu (t1/2: 0.4 h), 61Cu (t1/2: 3.3 h), 62Cu (t1/2: 9.7 min), 64Cu (t1/2: 12.7 h), and 67Cu (t1/2: 62.0 h)......

The labeling of probes with fluorine-18 [18F, β(+); 96.7%] continues to play a considerably important role in the development of positron emission tomography (PET) as a modality for both clinical research and clinical diagnoses. This review summarizes the strategies and recent developments in the fluorine-18 labeling of probes for PET imaging. Problems and issues relating to the practical production of fluorine-18 currently in widespread use are also discussed.

Positron Emission Tomography (PET) field and, in particular utilization of 68Ga radiometal is getting momentum. The development of new imaging agents for targeted, pre-targeted, non-targeted imaging and their clinical applications is accelerating worldwide. The pharmacopoeia monographs regarding generator produced 68Ga radionuclide and 68Ga-labeled somatostatin (SST) analogues are in progress. The number of commercial generators and automated synthesizers for 68Ga-labeling chemistry is increasing constantly. Development of a molecular imaging agent is a complex process including identification of the biological target, respective lead compound, synthesis of the imaging agent, its chemical characterization, pre-clinical, and clinical evaluation. The introduction of new radiopharmaceuticals and their accessibility are important factors determining the expansion of clinical nuclear medicine for early disease detection and personalized medicine with higher therapeutic efficiency. Further, the availability of the technology for GMP compliant automated tracer production can facilitate the introduction of new radiopharmaceuticals due to the ability to conduct standardized and harmonized multi-center studies for regulatory approval. This review reflects on the current status of 68Ga in PET field with the focus on the achievements in the chemistry as well as diversity and potential of the resulting tracers.

Development of targeted radionuclide therapy with 90Y labeled antibodies and peptides has gained momentum in the past decade due to the successes of 90Y-ibritumomab tiuxetan and 90Y-DOTA-Phe1-Tyr3-octreotide in treatment of cancer. 90Y is a pure β--emitter and cannot be imaged for patient-specific dosimetry which is essential for pre-therapeutic treatment planning and accurate absorbed dose estimation in individual patients to mitigate radiation related risks. This review article describes the utility of 86Y, a positron emitter (33%) with a 14.7-h half-life that can be imaged by positron emission tomography and used as an isotopically matched surrogate radionuclide for 90Y radiation doses estimations. This review discusses various aspects involved in the development of 86Y labeled radiopharmaceuticals with the specific emphasis on the radiochemistry and biological applications with antibodies and peptides.

The positron emitting isotope 89Zr is an ideal radionuclide for use in positron emission tomography (PET) imaging with monoclonal antibodies (mAbs). This article reviews the cyclotron physics of 89Zr production, and the chemical separation methods for isolating it from yttrium target material. 89Zr coordination with the bifunctional chelate desferrioxamine B is discussed, along with the common procedures for attaching the chelate to mAbs. The review is intended to detail the procedure for creating 89Zr labeled mAbs, going from cyclotron to PET.

Positron emission tomography (PET) is a powerful molecular imaging technology with the ability to image and monitor molecular events in vivo and in real time. With the increased application of PET radiopharmaceuticals for imaging physiological and pathological processes in vivo, there is a demand for versatile positron emitters with longer physical and biological half-lives. Traditional PET radionuclides, such as carbon-11 (11C) and fluorine-18 (18F), have relatively short half-lives (20 min and 110 min, respectively). Among the currently available positron emitters, the non-standard radiohalogen iodine-124 (124I) has the longest physical half-life at 4.2 d. This, combined with the well characterized radiochemistry of radioiodine, is contributing to the increasing utility of 124I in investigating slow and complex pharmacokinetic processes in clinical nuclear medicine and small animal PET imaging studies. This review will summarize the progress to date on the potential of 124I as a positron emitting nuclide for molecular imaging purposes, beginning with the production of 124I. Particular emphasis will be placed on the basic radiochemistry as it applies to the production of various 124I-labeled compounds, from small molecules, to biomolecules such as peptides and proteins, and finally to macromolecules like nanoparticles. The review will conclude by highlighting promising future directions in using 124I as a positron emitter in PET radiochemistry and molecular imaging.

The increasing use of positron emission tomography in preclinical and clinical settings has widened the demand for radiopharmaceuticals with high specificity that can image biological phenomena in vivo. While many PET tracers have been developed from small organic molecules labeled with carbon-11 or fluorine-18, the short half-lives of these radionuclides preclude their incorporation into radiotracers, which can be used to image biological processes that are not induced immediately after system perturbation. Additionally, the continuing development of targeted agents, such as antibodies and nanoparticles, which undergo extended circulation, require that radionuclides with half-lives that are complimentary to the biological half-lives of these molecules be developed. Copper radionuclides have received considerable attention since they offer a variety of half-lives and decay energies and because the coordination chemistry of cooper and its role in biology is well understood. However, in addition to the radiometal chelate, a successful copper based radiopharmaceutical depends upon the chemical structure of the entire radiotracer, which may include a biologically important molecule and a chemical linker that can be used to deliver the copper radionuclide to a specific target and modulate its in vivo properties, respectively. This review discusses the development of copper radiopharmaceuticals and the importance of factors such as chemical structure on their pharmacokinetics in vivo.

Cancer is a diverse disease with decisive pathobiology involving complex mechanisms. Recent advancements through research continue to focus on identifying vital targets and discovering multi-model therapies. It is essential to understand the disease processes and exploring the possible therapeutic strategies to save the lives of patients; however, the key factor remains the early diagnosis of the disease. In cancer therapy, it is very critical to identify ‘targets’ that will serve as limiting factors to regulate the disease by inhibiting tumor growth and metastasis. Emergence of drug resistance is one of the main reasons for the failure of drug therapy that leads to disease progression or recurrence, which may be lethal for patients. This hot topic issue on ‘Contemporary Approaches in Cancer Therapy’ primarily focuses on molecules/factors associated with cancer therapy and drug resistance, apart from a research report on developing non-invasive strategies for cancer diagnosis. This special issue contains ten original manuscripts including six research articles, one research report and three review articles. The research article by Achari et al. presents interesting data showing the application of multi-drug resistance (MDR)-1 modulating agent, chebulagic acid, for improving the efficacy of standard chemotherapeutic regimen in hepatocellular carcinoma. The intricacy of MDR in chemotherapy is a serious concern and this research article enlightens the importance of using MDR-1 modulating agents for addressing such an issue in cancer therapy. The research report written by Ozturk et al. provides interesting preliminary data on a non-invasive method for the diagnosis of breast cancer. Sialic acid is reported to be altered in both blood and saliva of various cancer patients. In this research report, authors elucidate an important study using patients' saliva to exploit a non-invasive predictive marker for breast cancer. Direct cell-cell communication is implicated in cellular differentiation and directs cellular function in mammary glands. Researchers are developing a novel strategy to exploit gap junction intracellular communication (GJIC) to enhance the efficacy of anti-cancer agents. The research article from Bernzweig et al. reveals the results of testing small molecules that modulate GJIC in combination with other known anti-cancer drugs to achieve higher response for the treatment of breast cancer. High expression of heat shock proteins (Hsp) such as hsp90 in tumor cells correlates with poor prognosis and aggressive disease. The research article by Chaturvedi et al. elucidates that targeting cyto-architecture and extracellular matrix of tumor cells through inhibiting hsp90 as a distinctive strategy in combating cancer. Designing potent and selective Src kinase inhibitors as anticancer agents is gaining significance since Src kinase mutations and/or overexpression have been implicated in the development of several malignancies including colon, breast, and lung cancers. Fallah-Tafti et al. reports for the first time that developing 4-aryl substituted derivatives of 2-amino-7-dimethylamino- 4H-chromene-3-carbonitrile may serve as potential Src kinase inhibitors with anti-cancer properties. Aberrant methylation of tumor suppressor genes (TSG) is an important epigenetic event in cancer, including multiple myeloma (MM). DNA methylation, the addition of a methyl group to the carbon-5 position of cytosine residues, is a key epigenetic modification controlling the expression of interleukin-6 (IL-6) which is associated with the pathogenesis of MM. Ingersoll et al. shows that IL-6-dependent pathway may regulate hypermethylation of TSG in MM. A number of studies on natural products reported that moderate consumption of tea may protect against several forms of cancer. It is evident that drug metabolizing enzymes such as cytochrome P450 (CYP) are involved in the bioactivation of precarcinogens and detoxification of ultimate carcinogens. Investigations by Maliakal et al. describes the effect of tea consumption on modulating CYP and phase II conjugating enzymes, and their association in the chemopreventive effect against esophageal tumorigenesis.....

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) specific inhibitors are antiinflammatory agents that have also shown to be useful in anticancer therapy. The effects of chebulagic acid (CA), a benzopyran tannin from Terminalia chebula having COX-2/5-LOX dual inhibitory properties, on the sensitivity of doxorubicin (Dox) in human hepatocellular carcinoma cell line HepG2 were studied in the present investigation. CA increased the accumulation of Dox in a concentration dependant manner and also enhanced the cytotoxicity of Dox in HepG2 cells by 20 folds. Quantitation of interaction by calculating Combination Index (CI) showed a strong synergistic interaction between CA and Dox in terms of cell growth inhibition. Calculation of dose reduction index (DRI) for CA-Dox combinations also showed a significant decrease in the dosage of Dox in the presence of CA. The induction of multidrug resistance protein-1 (MDR-1) expression by PGE2, a metabolite of COX-2, and its downregulation by COX-2 knockdown or CA implies that the enhanced sensitivity of HepG2 cells to doxorubicin by CA is mediated by the downregulation of MDR1 expression, via COX-2-dependent mechanism. Further studies reveal the inactivation of signal transduction pathways involving Akt, ERK, JNK and p38 and the transcription factor NF-κB in the CA induced down regulation of MDR1. The present study shows the efficacy of CA to overcome MDR-1 mediated drug resistance in HepG2 cells through COX-2 dependant modulation of MDR-1.

Breast cancer is the most common cancer in women living in the Western world, even though it occurs worldwide. Cancer and cancer therapy induce multiple oral complications including dental and periodontal disease. Saliva is a complex and dynamic biologic fluid, which reflects both oral and systemic changes. While saliva is an easily accessible body fluid, there has been little effort to study its value in cancer diagnosis. Sialic acids (SA), the end moieties of the carbohydrate chains, are biologically important and essential for functions of glycoconjugates that are reported to be altered in both blood and saliva of various cancer patients. Increased sialylation has been shown to be a characteristic feature in cancer tissue and blood in breast cancer patients. However, there is no data about salivary SA in breast cancer. The aim of this study was to evaluate salivary total sialic acid (TSA) levels in breast cancer patients who were under chemotheraphy. The study included 15 breast cancer patients in different stages and 10 healthy individuals as age-matched controls. Unstimulated whole saliva was collected. Salivary total protein and SA levels were determined. Flow rate was calculated from salivary volume by the time of secretion. Salivary SA was significantly higher and total protein was lower in breast cancer patients compared to controls. It is concluded that sialylation may be increased in saliva of patients with breast cancer as the same way for cancer tissue and for blood. Increased salivary SA may therefore be useful as a non-invasive predictive marker for breast cancer patients and for the prevention and management of oral complications of cancer and cancer therapy to improve oral function and quality-of-life. The effects of different types of chemotherapies and different stages of the disease on salivary SA levels and salivary sialo-glycomic are worthy of being further investigated in breast cancer patients.

Cancer cells exhibit many defects in cell communication that contribute to the loss of tissue homeostasis (excess cell proliferation, invasion, and metastasis). The process of cancer formation causes a disruption in cell homeostasis, affecting the ability to respond to extracellular signals, as well as triggering some intracellular events which alter gap junctional intercellular communication (GJIC). Previous research has shown that the first two generations of substituted quinolines have anti-cancer effects in human breast cancer cells. This report presents the synthesis and bioactivities of third generation substituted quinolines. Scrape load/dye transfer studies showed that 100 nM of PQ15, a third generation substituted quinoline, causes a 4.5-fold increase of gap junction activity in T47D breast cancer cells. Furthermore, a significant decrease of cell proliferation and viability was observed in the presence of 200 nM PQ15 compared to control. The expression of α-survivin was reduced to <40% in the treatment of 200 nM PQ15 compared to solvent alone. Alpha survivin expression is upregulated in human cancers and associated with resistance to chemotherapy, suggesting that α- survivin prolongs the survival of cancer cells. Thus, it has been shown that substituted quinolines stimulate gap junction activity, decrease alpha survivin expression, and subsequently inhibit cancer cell growth. Our findings demonstrate that PQ15 has a promising role in exerting anti-cancer activity in human breast cancer cells.

Pharmacological inhibition of Hsp90 in tumor cells induces anticancer effects through the destabilization of several oncogenic signaling molecules. Although there were reports that Hsp90 inhibition compromises cellular integrity, how this affects the cell adhesion through extracellular matrix (ECM) and integrin signaling is not known. Using human neuroblastoma (IMR-32), cervical (HeLa) and breast (MCF-7) cancer cells, and mouse embryonal carcinoma (PCC-4) cells, and using different substratum, glass, plastic, fibronectin, and matrigel, we demonstrate 17AAG induced alterations in integrin cross-linking with the actin cytoskeleton. The 17AAG treatment of cells resulted in decreased mRNA levels and confined surface expression of three major beta1 family of integrins namely α2, α3, and α5 in IMR-32, HeLa and PCC-4 cells, but showed induced mRNA levels and surface expression in MCF-7 cells. Loss of surface expression of integrins correlated with inhibition of focal adhesion kinase (FAK) and mitogen regulated kinase (ERK1/2) activities, in contrast, induced integrin expression in MCF-7 correlated with activation of these kinases. Prolonged treatment but not the pretreatment (2 h) with 17AAG resulted in destabilized actin cytoskeleton, delayed wound repair, and limited colony forming ability of tumor cells on soft agar. Conclusively, we show that Hsp90 inhibition targets cell adhesion, which may relate to the inhibition of integrin signaling and inhibition of integrin-cytoskeleton crosslinking.

Src kinase mutations and/or overexpression have been implicated in the development of a number of human cancers including colon, breast, and lung cancers. Thus, designing potent and selective Src kinase inhibitors as anticancer agents is a subject of major interest. A series of 4-aryl substituted derivatives of 2-amino-7-dimethylamino-4H-chromene- 3-carbonitrile were synthesized using one-pot reaction of appropriate substituted aromatic aldehydes, malononitrile, and 3-(dimethylamino)phenol in the presence of piperidine. All 23 compounds were evaluated for inhibition of Src kinase and cell proliferation in human colon adenocarcinoma (HT-29) and leukemia (CCRF-CEM) cell lines. Among the tested compounds, 2-chlorophenyl- (4c), 3-nitrophenyl- (4h), 4-trifluoromethyphenyl- (4i), and 2,3-dichlorophenyl- (4k) substituted chromenes showed Src kinase inhibitory effect with IC50 values of 11.1-18.3 μM. Compound 4c was relatively selective against Src (IC50 = 11.1 μM), when compared with selected kinases, epidermal growth factor receptor (EGFR, IC50 > 300 μM), C-terminal Src kinase (Csk, IC50 = 101.7 μM), and lymphocyte-specific protein tyrosine kinase (Lck, IC50 = 46.8 μM). 3-Chlorophenyl substituted thiazole (4v) and 2-chlorophenylsubstituted thiazole (4u) chromene derivatives inhibited the cell proliferation of HT-29 and CCRF-CEM by 80% and 50%, respectively, at a concentration of 50 μM. The data indicate that 4H-chromene-3-carbonitrile scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds.

Aberrant methylation of tumor suppressor genes (TSG) is an important epigenetic event in cancer, including multiple myeloma (MM). Interleukin-6 (IL-6), which plays a significant role in the pathogenesis of MM, also regulates DNA methylation. However, attempts to bring IL-6 blockade to the clinic have had limited success. We hypothesize that IL-6 regulation of hypermethylation may be an important pathway leading to rational chemotherapeutic/anti-IL-6 combinations. We first studied the correlation of IL-6 expression and dependence in MM cell lines: U266B1, RPMI8226, and KAS6/1. We confirmed that KAS6/1 is IL-6-dependent whereas U266B1 and RPMI8226 cells are IL-6-independent and that blocking IL-6 inhibited the growth of U266B1 (36% inhibition; p<0.05) and KAS6/1 (68% inhibition; p<0.01), but not the RPMI8226 cells. Using RT-PCR, we showed that U266B1 cells express IL-6, but RPMI8226 and KAS6/1 cells do not. This IL-6 expression pattern correlates with the anti-IL-6 inhibition findings. To correlate IL-6 sensitivity with hypermethylation of TSG, we investigated promoter methylation of CDH1 and DcR1. We found that the promoter of DcR1 and CDH1 is methylated in U266B1 cells and un-methylated in RPMI8226 cells. Furthermore, the DcR1 promoter was un-methylated in KAS6/1 cells. These data support our hypothesis that an IL-6-dependent pathway may regulate hypermethylation of TSG in MM. Newer chemotherapeutic agents that affect methylation are being studied in combination with IL-6 blockade.

Tea is a popular, socially accepted, drink that is enjoyed by millions of people. A growing body of evidence suggests that moderate consumption of tea may protect against several forms of cancer. It is also known that bioactivation of precarcinogens and detoxification of ultimate carcinogens are carried out mainly by drug metabolizing enzymes such as cytochrome P450 (CYP). The present study investigates the effect of tea consumption on modulating CYP and phase II conjugating enzymes, and their association in the chemopreventive effect against esophageal tumorigenesis using both in vitro and in vivo techniques. Female Wistar rats were given aqueous solutions (2% w/v) of six different teas, standard green tea extract (GTE) (0.5% w/v), and dandelion tea (2% w/v) as the sole source of fluid for two weeks prior to and during the entire period of tumor induction (12 weeks). Animals were gavaged with 0.5 mg/kg N-nitrosomethylbenzylamine (NMBA) twice weekly for 12 weeks for esophageal tumor induction and the activities of different CYP isoforms and phase II enzymes were determined in the liver microsomes or cytosols. GTE, green tea and Dandelion tea caused decrease in tumor multiplication, tumor size and tumor volume; however, none of these tea preparations altered tumor incidence. No appreciable changes in drug metabolizing enzyme activity were observed in the treatment groups. Thus, the modulations in the activities of CYP 1A1/ 1A2 and CYP2E enzymes, by pre-treatment with green and dandelion teas, observed in our earlier experiments, seem to be compensated by the tumor inducing agent, NMBA. The balance between phase I carcinogen- activating enzymes and phase II detoxifying enzymes could be important in determining the risk of developing chemically-induced cancer and the present study in conjunction with the previous observations suggest a possible role of drug metabolizing enzymes in the anticancer effect of tea.

Nano Drug Delivery, as a treatment method against brain tumors, is a progressing area in the field of precise targeted drug administration methodology. The unresolved problems related to chemotherapy, other invasive therapeutic procedures and various obstructions offered by biological barriers are circumvented by nanodrug delivery. Recent dramatic developments in nanotechnology have created a lot of nano-devices which could be used against cancer. Infiltration, modulation of the Blood Brain Barrier, camouflaged from immune defense mechanism and the specific targeting of cancer affected cells are a few of the attractive features of nanodevices. We present here a review of newly evolved nanoplatforms in brain tumor therapy in which careful attention has been paid into various form nanoparticles, useful targeting ligands, altered chemotherapy agents and existing tumor therapy methods using nanotechnology.

Cancer represents a major cause of overall mortality, second to cardiovascular disorders. Cancer patients frequently encounter hypercoagulable states, with recurrent thromboembolic events due to the impact of cancer cells and chemotherapy/radiotherapy on the coagulation cascade. The expression of highly procoagulant proteins have been implicated to involve in tumor cell-induced thrombin generation, leading to platelet activation and fibrin clot formation. These include binding of heparin to angiogenic growth factors (e.g., basic fibroblast growth factor and vascular endothelial growth factor); modulation of tissue factor (TF); and enhanced TF-pathway-inhibitor release, and inhibition of matrixdegrading enzymes. The classical anticoagulant (unfractionated heparin; UFH), and its derived low-molecular-weight heparins (LMWH) are polypharmacologic agents. These anticoagulants are composed of oligosccharides with structural/ molecular heterogeneity. Heparins bind to wide range of molecules via electrostatic interactions with the glycosaminoglycan chains, and hence possess numerous therapeutic properties beyond their anticoagulant effects, including anticancer potentials. Recent studies demonstrate that UFH and LMWH fractions interfere with various cellular/inflammatory processes and reduce mortality/morbidity in malignancy-associated thrombosis and vascular disorders. There are certain weaknesses of heparins, particularly when patients receiving prolonged therapy, including bleeding complications. Paradoxically, many individuals receiving heparin anticoagulants develop antibodies against the complex formed between heparin and platelet factor 4 because of massive platelet/cellular activation and hypercoagulable state, resulting in clinical manifestation referred to as heparin-induced thrombocytopenia (HIT) syndrome. Increased risk of venous thromboembolic events are likely in individuals with malignancy-associated thrombosis coupled with underlying HIT pathogenesis. This article reviews the existing knowledge about the experimental/clinical anti-cancer properties of heparin anticoagulants and provide a rationale for future research.

Transcription factors are proteins that regulate gene expression by binding to specific DNA sequences within gene promoter regions. Specificity protein (Sp) family transcription factors play a critical role in various cellular processes and have been shown to be associated with tumorigenesis. The Sp family consists of several members that contain a highly conserved DNA-binding domain composed of three zinc fingers at the C-terminus and serine/threonine- and glutamine- rich transactivation domains at the N-terminal. Sp1 is elevated in several malignancies including prostate cancer and is associated with the prognosis of patients. Sp1, Sp3, and Sp4 regulate a variety of cancer associated genes that are involved in cell cycle, proliferation, cell differentiation, and apoptosis. Studies have shown that in prostate cancer, Sp1 regulates important genes like androgen receptor, TGF-β, c-Met, fatty acid synthase, matrix metalloprotein (MT1-MMP), PSA, and α-integrin. These results highlight the importance of Sp1 in prostate cancer and emphasize the potential therapeutic value of targeting Sp1. Several strategies, including the use of natural and synthetic compounds, have been used to inhibit Sp1 in prostate cancer. These include polyphenol quercetin, betulinic acid, acetyl-11-keto-beta-boswellic acid, tea phenols, isothiocyanates, thiazolidinediones, arsenic trioxide, and selenium. This review will describe the association of Sp1 in prostate cancer with a special emphasis on some of the agents tested to target Sp1 for the treatment of this malignancy.